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REVIEW ARTICLE
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The metabolic syndrome and chronic kidney 70
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8 Q1 disease 72
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10 75
11 76
12 Q5 XIN ZHANG, and LILACH O. LERMAN
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13 78
ROCHESTER, MINN
14 79
15 80
16 81
17 82
18 The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including 83
19 insulin resistance (IR), dyslipidemia, and hypertension, which may also foster devel- 84
20 opment of chronic kidney disease. The mechanisms of MetS-induced kidney disease 85
21 are not fully understood. The purpose of this review is to summarize recent discoveries 86
22 87
regarding the impact of MetS on the kidney, particularly on the renal microvascula-
23 88
24
ture and cellular mitochondria. Fundamental manifestations of MetS include IR and
adipose tissue expansion, the latter promoting chronic inflammation and oxidative 89
25 90
26 stress that exacerbate IR. Those in turn can elicit various kidney injurious events
91
27 through endothelial dysfunction, activation of the renin-angiotensin-aldosterone
92
28 system, and adipokine imbalance. Inflammation and IR are also major contributors 93
29 to microvascular remodeling and podocyte injury. Hence, these events may result in 94
30 hypertension, albuminuria, and parenchymal damage. In addition, dyslipidemia 95
31 and excessive nutrient availability may impair mitochondrial function and thereby 96
32 promote progression of kidney cell damage. Elucidation of the link between MetS 97
33 98
and kidney injury may help develop preventative measures and possibly novel ther-
34 99
35
apeutic targets to alleviate and avert development of renal manifestations. (Transla-
tional Research 2016;-:111) 100
36 101
37 102
38 Q2 Abbreviations: --- --- 103
39 104
40 105
41 106
42 107
43 108
44 EPIDEMIOLOGY circumference); (2) elevated triglyceride levels; (3)
109
45

A
ccording to the American Heart Association, low high-density lipoproteins; (4) hypertension; and 110
46 (5) elevated fasting glucose.1 The International Dia- 111
47
individuals with the metabolic syndrome
betes Federation criteria are similar, but more specific 112
48 (MetS) show 3 or more of the following con-
regarding the definition of central obesity categorized 113
49 ditions: (1) central or abdominal obesity (by waist 114
50 by country or ethnic group.2 A waist circumference
115
51 greater than 94 cm for Europid males is considered cen- 116
52 tral obesity, whereas 90 cm are indicative in Asian 117
53 From the Division of Nephrology and Hypertension, Mayo Clinic,
118
males.
54 Rochester, Minn.
119
55 Although greater awareness of MetS may have
Submitted for publication September 7, 2016; revision submitted 120
56 contributed to improvements in treatment of risk factors
November 22, 2016; accepted for publication December 2, 2016. 121
57 Reprint requests: Lilach O. Lerman, Division of Nephrology and Hy- like hypertension and diabetes, nearly 35% of all adults 122
58 pertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; and 50% of those 60 years or older were still estimated 123
59 e-mail: lerman.lilach@mayo.edu. to have MetS.3 MetS is an important contributor to car- 124
60 125
61 1931-5244/$ - see front matter diovascular morbidity and mortality. Among 12,561
126
62 2016 Elsevier Inc. All rights reserved. subjects from the United States Third National Health
127
63 http://dx.doi.org/10.1016/j.trsl.2016.12.004 and Nutrition Examination Survey, 13.3% of the excess

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128 cardiovascular mortality in the United States could be MICROVASCULAR REMODELING 192
129 attributed to higher prevalence of MetS and MetS with 193
130 We and others have observed that in humans and 194
131
baseline cardiovascular disease.4 Moreover, MetS often animals, MetS induced renal parenchymal damages 195
132 progresses to frank type-2 diabetes, particularly in sub- such as tubular atrophy and interstitial fibrosis.9,15 196
133 jects with hyperglycemia. In a recent study of 28,209 Microvascular remodeling manifesting as arterial and 197
134 patients, yearly conversion rates to diabetes were only 198
135
arteriolar sclerosis within kidney lesions in patients 199
0.6% in MetS individuals with normoglycemia or with MetS have also been observed,9 and ultrasound re-
136 200
137
mild hyperglycemia, but 2.5% in those with intermedi- vealed elevated resistive indices in intrarenal interlobar 201
138 ate hyperglycemia (6.17.0 mmol/L),5 leading to partic- arteries,16,17 indicating vasoconstriction and 202
139 ularly elevated risk for cardiovascular complications. microvascular remodeling. Direct evidence for the 203
140 Studies have suggested that individuals with MetS are 204
141
effects of MetS on microvessels has been obtained 205
also at increased risk for developing chronic kidney dis- from studies in animal models. In rats, a 6-week MetS
142 206
143
ease (CKD), reflected by microalbuminuria6,7 and renal diet (60% fructose) induced wall thickening in outer 207
144 dysfunction.8 Patients with 12 traits of MetS are twice cortical and juxtamedullary afferent arterioles,18 208
145 more likely to have microalbuminuria than those without mimicking arteriolar sclerosis observed in humans. In 209
146 the syndrome, and the likelihood rises to 130% in those 210
147
MetS Ossabaw pigs, dysregulated angiogenesis was 211
with more than 3 traits.6 In a study including 5800 pa- observed after a 16-week diet, accompanied by
148 212
149
tients with type-2 diabetes, MetS independently pre- increased tissue fibrosis,15 partly due to elevation of 213
150 dicted the new onset of CKD.4 After adjustments for Angiotensin II (AngII), consistent with activation of 214
151 diabetes and hypertension, MetS remained an indepen- the renin-angiotensin-aldosterone system observed in 215
152 dent risk factor contributing to the development of 216
153
MetS.19 Accumulation of visceral adipose and fat infil- 217
CKD, defined as fall of the kidney function over a tration of the kidney may also induce inflammation-
154 218
155
9-year follow-up.8 Patients with MetS undergoing ne- driven neovascularization through multiple cytokines 219
156 phrectomy also showed a higher prevalence of features that are enriched in adipose tissue such as tumor necro- 220
157 characterizing CKD, including global and segmental sis factor (TNF)-a and interleukin-6 (IL-6).20,21 221
158 glomerulosclerosis and loss of renal function, compared 222
159
Using a 3-dimensional micro-CT, we found that at its 223
with those without MetS.9 Recent studies also suggest early stage MetS in fact stimulated microvascular prolif-
160 224
161
that the presence of MetS before renal transplantation eration in the kidney.22,23 The increase in microvascular 225
162 predicts subsequent development of new-onset diabetes density (Fig 1, Top) was associated with the upregulated 226
163 after transplantation, and the presence of MetS after expression of vascular endothelial growth factor,22 227
164 transplantation adversely influenced allograft sur- 228
165
possibly secondary to oxidative stress24 commonly 229
vival.10,11 Over an 18-month follow-up post-transplanta- seen in MetS, and hyperinsulinemia that directly in-
166 230
167
tion, the hazard ratio for creatinine elevation was 2.6 and creases vascular endothelial growth factor production.25 231
168 patient survival was significantly diminished.10 These The small microvessels (2040 mm) that prolifer- 232
169 observations establish MetS as a trigger for renal injury ated22,23 may contribute to maintain renal perfusion, 233
170 in CKD, which magnifies the adverse impact of other in- 234
171
and may initially account for elevated renal blood flow 235
sults. Given the central role of the kidney in maintenance and glomerular filtration rate (GFR) that characterize
172 236
173
of bone homeostasis,12 MetS may also contribute to the early stage of MetS. However, those newly 237
174 bone mineral disorders in these subjects.13 generated vessels often have disorganized architecture, 238
175 The pathways activated by MetS to induce kidney dis- because following a 16-week MetS diet they become 239
176 ease are not fully understood. Over the past few years, 240
177
more torturous,23 suggesting that at the later stage of 241
studies have identified several new injurious pathways MetS intrarenal vessels may be dysfunctional and unsta-
178 242
179
that MetS activates in the kidney.14 Central tenets of ble. In addition, sustained mechanical strain on glomer- 243
180 MetS include insulin resistance (IR) and chronic inflam- ular capillaries due to hyperfiltration likely increases 244
181 mation, a major contributor to microvascular remodel- propensity for microvascular loss.26 245
182 ing. In addition, dyslipidemia and excessive nutrient 246
183
Furthermore, under physiological condition insulin 247
availability may induce mitochondrial dysfunction; adi- may regulate GFR through local renal vasodilation,
184 248
185
pokines, the renin-angiotensin system, and oxidative which can be blocked by indomethacin27 and 249
186 stress may permit development of hypertension. Better augmented by activation of endothelial nitric oxide 250
187 understanding of the mechanisms by which MetS in- (NO) synthase.28 However, this effect of insulin might 251
188 jures the kidney may direct future studies and possibly 252
189
be lost over time in MetS subjects with IR,29 who 253
novel therapeutic targets to alleviate and prevent the manifest endothelial dysfunction due to downregu-
190 254
191
development of renal manifestations of MetS. lated expression of eNOS and increased endothelin-1 255

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288 Fig 1. ---. Q4
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291 levels.30 Uric acid (UA), which is often elevated in between MetS and the severity of intrarenal 355
292 MetS, also inhibits NO production, thus contributing microvascular remodeling in stenotic kidneys needs 356
293 to endothelial dysfunction.18 Renal microvascular to be considered during management of these patients. 357
294 endothelial dysfunction increases glomerular capillary 358
295 359
wall permeability and albuminuria, which may also
296 INFLAMMATION AND INSULIN RESISTANCE 360
297 promote glomerular capillary loss21 in prolonged 361
298 MetS and progression of renal injury. Indeed, MetS Low-grade chronic inflammation is a hallmark of 362
299 patients show a steeper decrease in kidney function MetS32 and its severity seems to depend on the prevalent 363
300 over time compared with non-MetS patients, suggest- number of components of MetS.33 In fact, the pivotal 364
301 365
ing limited renal reserve, which might be the conse- role of metabolically induced inflammation is under-
302 366
303 quence of kidney vascular remodeling and scored by the proposed term metaflammation.34 367
304 parenchymal damage in MetS.9 Moreover, MetS Animal studies have highlighted the kidney as a target 368
305 may impose vascular remodeling and accelerate organ often involved in the inflammatory response.15,35 369
306 development of atherosclerotic lesions. Renal artery A 16-week MetS diet in pigs elevated the levels of circu- 370
307 371
stenosis, detected in 16% patients with cardiovascular lating oxidized low-density lipoprotein and soluble (s)
308 372
309 events,31 further decreases blood supply to the kidney E-selectin that recruits inflammatory cells,15 and 373
310 and exacerbates renal damage. Indeed, in poststenotic increased infiltration of proinflammatory macrophages 374
311 swine kidneys, MetS precipitates or magnifies loss of in the kidney (Fig 1, Bottom), accompanied by the 375
312 microvessels,15 thereby aggravating tissue injury. This development of glomerulosclerosis.15 Similarly, Zucker 376
313 377
synergistic interaction between MetS and renal fatty diabetic rats show macrophage infiltration in the
314 378
315 ischemia is associated with increased oxidative stress tubular-interstitium space and neutrophils in peritubular 379
316 and inflammation, which disrupt microvascular stabil- capillaries, associated with wide-spread fibrosis.35 380
317 ity.15,23 As renal artery stenosis is increasingly Hence, inflammation may mediate the development of 381
318 observed in the aging modern society, the link renal fibrosis and glomerulosclerosis in MetS. 382
319 383

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384 One of the plausible hypotheses is that MetS induced Evidence indicated that IR is not infrequently associ- 448
385 disruption in many physiological regulatory systems ated with CKD.47,48 In a 9-year study, the severity of IR 449
386 450
387
due to excessive energy intake, provoking stressor stim- was directly related to the risk of developing CKD.48 In 451
388 uli that subsequently trigger inflammatory and oxidative slightly overweight nondiabetic patients, the prevalence 452
389 pathways.34 This response might aim to block major of CKD significantly and progressively rises with 453
390 anabolic signaling pathways, such as the insulin/insulin increasing levels of serum insulin and IR.49 As mentioned 454
391 growth factor (IGF) pathway, thereby diverting energy earlier, hyperinsulinemia may induce glomerular hyper- 455
392 456
393
sources from synthetic pathways.34 In vitro studies filtration, endothelial dysfunction, and increased vascular 457
394 demonstrated that the inflammatory mediator IL-6 ex- permeability,50 leading to albuminuria. In nondiabetic 458
395 erts inhibitory effects on IGF-1 signaling pathways subjects, even a short-term insulin infusion increases uri- 459
396 (extracellular-regulated protein kinase [ERK]1/2 and nary albumin excretion.51 In turn, albumin in the tubular 460
397 Akt) by blocking its receptor substrate (IRS)-1,36 or lumen may lead to tubulointerstitial injury and fibrosis.52 461
398 462
399
by increasing its clearance.37 The link between IR and kidney disease might be attribut- 463
400 Adipose tissue expansion, a central tenet of MetS, rep- able to the dependence of the kidney on insulin, which 464
401 resents a major source of inflammatory cytokines. In hu- binds to all nephron cells, including the glomerulus and 465
402 man subjects, adipocyte size correlates with levels of the entire length of the renal tubules.53,54 Particularly, 466
403 TNFa, IL-6, and high-sensitivity C-reactive protein the glomerular podocytes, major components of the 467
404 468
405
(CRP).38 Experimental studies in MetS animals have glomerular filtration barrier, have higher expression of 469
406 shown substantial infiltration of inflammatory macro- insulin receptors compared with endothelial and 470
407 phages and TNF-a in the abdominal and perirenal fat tis- mesangial cells,55 and insulin may control podocyte 471
408 sue,15,39 which could serve as a channel for contractility associated with glomerular perme- 472
409 inflammatory cytokines to access the kidney. In ability.56,57 Conceivably, changes in the abundance or 473
410 474
411
addition, renal arterial endothelial function was sensitivity of insulin receptors in MetS may regulate 475
412 blunted when incubated in vitro with perirenal fat renal physiology and/or pathology. Furthermore, 476
413 harvested from MetS pigs, and restored by TNFa elevated insulin levels have been found to stimulate 477
414 inhibitor, substantiating its injurious effect on the renal IGF-1 production, which increases connective tissue 478
415 vasculature.39 Weight loss improves both inflammatory growth factor, causing renal fibrosis.58 Indeed, insulin- 479
416 480
417
(C-reactive protein, TNF-a, IL-6, and leptin) and anti- sensitizing compounds, such as thiazolidinediones 481
418 inflammatory (adiponectin) markers in human sub- (TZD), abrogate interstitial fibrosis in Zucker obese rats 482
419 jects,40,41 and MetS rats treated with anti-inflammatory fed a high-protein diet.59 These findings suggest that 483
420 mycophenolate mofetil showed reduced systemic and the interaction of insulin with its receptor bears direct 484
421 renal inflammation and limited renal fibrosis.35 There- ramification for renal structural and functional impair- 485
422 486
423
fore, measures to control inflammation in MetS may ment in MetS. As hyperglycemia becomes more evident, 487
424 be beneficial for the kidney. advanced glycation end products (AGEs) also participate 488
425 Even in the absence of other coexisting MetS compo- in kidney damage via their receptors on podocytes and 489
426 nents, inflammatory mediators alone can trigger IR. For endothelial cells. Deposition and activation of AGEs pro- 490
427 example, in humans uremia can cause IR by disrupting mote cellular hypertrophy and apoptosis, as well as 491
428 492
429
insulin signaling.42 In vitro, stimulated macrophages inflammation.60 Whether systemic levels of AGEs corre- 493
430 produce IL-1b and IL-18, contributing to pancreatic late with severity or progression of kidney damage in 494
431 b-cell death with chronic hyperglycemia and progres- MetS needs to be examined. 495
432 sion of diabetes.43 These observations suggest that More recently, adipocytokines linked to IR, low-grade 496
433 inflammation can be upstream to metabolic derange- inflammation, endothelial dysfunction, and vascular 497
434 498
435
ment. Clinical studies have found that Salsalate, a pro- damage have been proposed to modulate kidney func- 499
436 drug of salicylate which suppresses inflammation, tion.61 Adiponectin, which is linked to insulin sensi- 500
437 attenuates IKKb/NF-kB activity, improves glycemic tivity, regulates the function of podocytes, major sites 501
438 control in patients with type-2 diabetes,44 and alleviates of adiponectin receptor in the kidney.62 Mice with 502
439 IR.45 TNF-a blockade improved fasting glucose and reduced or abolished expression of adiponectin exhibit 503
440 504
441
improved the levels of anti-inflammatory adiponectin exacerbation of podocyte injury, albuminuria, and renal 505
442 in obese subjects with abnormal glucose homeostasis.46 fibrosis compared with wild-type animals.63-65 The 506
443 Clearly, the cause and effect relationship between regulatory role of adiponectin on podocyte function is 507
444 inflammation and MetS remains to be discerned, and likely mediated through the 50 AMP-activated protein ki- 508
445 the ability of management of inflammation to alleviate nase (AMPK) pathway, and adiponectin-knockout mice 509
446 510
447
kidney injury in MetS warrants further studies. exhibit increased albuminuria and fusion of podocyte 511

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512 foot processes. In cultured podocytes, adiponectin dividual gains weight, each podocyte must undergo me- 576
513 administration was associated with increased activity chanical stretch to cover a larger surface area to 577
514 578
515
of AMPK, and both adiponectin and AMPK activation accommodate the increased glomerular volume,77 re- 579
516 reduced podocyte permeability to albumin and podocyte sulting in decreased podocyte density and increased 580
517 dysfunction.64 foot process width in adults with ORG.78 Podocyte 581
518 Conversely, serum levels of leptin, which regulate number increases in size in animals fed ad libitum in 582
519 hunger and satiety, are 5- to 10-fold higher in obese proportion to the extent of glomerular hypertrophy at 583
520 584
521
than in healthy individuals. In vitro, leptin induces the early stage.79 Over time, when podocyte enlarge- 585
522 glomerular mesangial cell hypertrophy,66 which subse- ment is no longer proportional to glomerular hypertro- 586
523 quently increases the amount of filtered protein and al- phy, podocytes fail and detach causing localized 587
524 bumin. Leptin has been shown to activate several cell denudation of the glomerular basement membrane, sub- 588
525 signaling pathways in a cell-specific manner. In vitro, sequent adhesions to the Bowman capsule and parietal 589
526 590
527
leptin can alter rat glomerular cell size via activation cell coverage, forming a nidus for development of 591
528 of the mitogen-activated protein kinase pathway segmental sclerosis,80 and resulting in proteinuria.81 592
529 through ERK 1/267 and hypertrophy in glomerular me- In addition, an average of 12% individuals with ORG 593
530 sangial cells via activation of phosphoinositide 3-kinase progress to focal segmental glomerulosclerosis 594
531 and ERK1/2.66 Leptin enhanced tissue growth factor (FSGS), which typically affects hypertrophied 595
532 596
533
(TGF)-b/Smad signaling in rat kidney fibroblasts, and glomeruli.82,83 Although those pathological alterations 597
534 leptin-deficient ob/ob mice had significant reduction can be prevented by calorie restriction,79 development 598
535 in TGF-b mRNA levels, Smad-2/3 activation, and to focal segmental glomerulosclerosis is often irrevers- 599
536 fibrotic tissue.68 ible and may eventually lead to end-stage renal 600
537 Resistin, an adipose sensor that contributes to disease.81 601
538 602
539
obesity,69 is also independently associated with albumin 603
excretion.70 Although the mechanisms of resistin- OXIDATIVE STRESS AND MITOCHONDRIAL
540 604
DYSFUNCTION
541 related kidney injury are less clear, studies have shown 605
542 that it upregulates the expression of intercellular adhe- Oxidative stress, characterized by elevated reactive 606
543 sion molecule-1 and vascular cell adhesion molecule- oxygen species (ROS) levels, causes damage to proteins, 607
544 608
545
1.71 In addition, both leptin and resistin enhance renal lipids, and DNA, and has been proven to play an impor- 609
546 sympathetic nerve activity,72 the latter possibly via tant role in MetS.84,85 In humans, lipid peroxidation, 610
547 phosphatidylinositol 3-kinase.73 represented by plasma thiobarbituric acid reactive 611
548 Therefore, IR and dysregulated adipokines in concert substance and urinary 8-epi-prostaglandin-F2a, corre- 612
549 target different renal cell types via various pathways to lates with BMI and waist circumference.86 613
550 614
551
elicit kidney disease in MetS. Nonetheless, while IR is A major source of ROS MetS is the NADPH oxidase 615
552 speculated as an important mediator of MetS-related (NOX) family of enzymes, and accumulating evidence 616
553 CKD,19 its complex role in regulating renal function, has shown that NOX, particularly NOX1, 2, and 4 which 617
554 solute transfer, and blood pressure needs to be better are highly expressed in the kidney,87 plays vital roles in 618
555 defined. intrarenal oxidative stress. Upregulated by metabolic 619
556 620
557
factors, NOX leads to glomerular overproduction of 621
558 ROS in podocytes, endothelial cells, and mesangial 622
OBESITY
559 cells, which is closely associated with the initiation 623
560 Substantial evidence has shown that obesity directly and progression of kidney diseases. Exposure of 624
561 influences renal hemodynamics and structure. A cultured mouse podocytes to high glucose resulted in 625
562 626
563
1-month high-fat diet promptly increases the extracel- apoptosis, which involved increased NOX activity and 627
564 lular fluid and causes a shift in sodium balance.74 ROS production.88 The transgenic TG (mRen2)27 628
565 Elevated aldosterone levels due to activation of the rats, which harbor the mouse renin transgene and 629
566 renin-angiotensin-aldosterone system and increased renin-angiotensin system activation, show increases in 630
567 sympathetic activity in obesity are likely the major cul- systolic blood pressure, albuminuria, renal NOX activ- 631
568 632
569
prits that promote sodium retention75,76 by increasing ity, accompanied by periarteriolar fibrosis and podocyte 633
570 tubular reabsorption. Elevated salt reabsorption at the foot process effacement.89 NOX4 has also been identi- 634
571 segment proximal to the macular densa also induces a fied as a critical mediator of high glucose- or angio- 635
572 rise in GFR through tubuloglomerular feedback, tensin II-induced mesangial cell activation.90,91 Even 636
573 contributing to hyperfiltration. short exposure of vascular smooth muscle cells to 637
574 638
575
Yet, obesity-related glomerulopathy (ORG) may not AngII, which is often augmented in MetS, increases 639
be mediated solely by hemodynamic factors. As an in- mRNA expression of NOX1 and NOX4 several fold,92

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640 suggesting that NOX activity is Ang II-dependent.89 Therefore, MetS may affect renal mitochondrial 704
641 Furthermore, additional mechanisms in injured kidneys structure and function through several different 705
642 706
643
may exacerbate oxidative stress, resulting in a vicious pathways. 707
644 circle. TGF-b increased in the rat kidney fibroblasts Mitochondrial dysfunction might also cause or 708
645 the activity of both NOX2 and NOX4.93 Hence, there worsen IR.118 A 35% decrease of mitochondrial DNA 709
646 is close link between oxidative stress and kidney health. (mtDNA) density in peripheral blood cells precedes 710
647 Therapeutic strategies targeting oxidative stress may be development of type-2 diabetes in patients.119 Genetic 711
648 712
649
useful to prevent or alleviate kidney injury in MetS. studies also identified human mtDNA haplogroups that 713
650 The mitochondrion is an intracellular organelle can modulate susceptibility to type-2 diabetes.120 Inter- 714
651 crucial for handling ROS production, which when estingly, rosiglitazone, one of the TZDs that increase in- 715
652 excessive impairs cellular function. Under normal con- sulin sensitivity, also recovers mitochondrial electron 716
653 ditions, mitochondria extract energy stored in nutrients transport function in mice with aldosterone-induced 717
654 718
655
that drives work within the body,94-96 and a series of mitochondrial dysfunction.121 We have recently also 719
656 feedback and regulatory steps enables matching the found cardioprotective effects of mitochondrial- 720
657 rate of mitochondrial oxidative phosphorylation with targeted peptides in MetS122; yet, their effects on the 721
658 cellular ATP demands.97,98 As the kidney has high kidney remain to be explored. Taken together, mitochon- 722
659 energy demand and is rich in mitochondria, drial function is vital in sensing and modulating energy 723
660 724
661
mitochondrial dysfunction plays a critical role in the metabolism in MetS, and development of mitochondria- 725
662 pathogenesis of kidney diseases by affecting almost targeting therapeutics may potentially benefit patients 726
663 all renal cell types,99,100 including participating with MetS and associated tissue injury. 727
664 epithelial-mesenchymal transition which contributes 728
665 to the loss of functional parenchyma.101,102 729
666 HYPERTENSION 730
667
In the setting of MetS, excessive nutrient availability 731
668 supplies superfluous electrons to the respiratory chain, Hypertension is an important hallmark of MetS and a 732
669 while lack of physical activity results in low ATP de- common cause of kidney disease. Several mechanisms 733
670 mand, favoring mitochondrial dysfunction and dispro- link hypertension to MetS, among which obesity is a ma- 734
671 portionate superoxide formation.103 Several elements jor contributor. Obesity alone is associated with an in- 735
672 736
673
that prevail in MetS may further disrupt mitochondrial crease in the severity of hypertension and the number 737
674 function. Oxidized low-density lipoprotein increases of required antihypertensive medications, and impedes 738
675 mitochondrial membrane potential and impairs redox achieving blood pressure control.123 The direct link be- 739
676 status,104 leading to apoptotic events; it may also cause tween hypertension and dyslipidemia-induced obesity 740
677 vascular endothelial dysfunction by translocating mito- was shown in animal studies. In rabbits, blood pressure 741
678 742
679
chondrial proteins.105 Patients with diabetic nephropathy rises by 6% after a 1-week high-fat diet, and falls back 743
680 demonstrate lower gene expression of the renal mito- after resumption of normal diet.124 Adipocytes are rich 744
681 chondrial inner membrane organic anion transporters 1 sources of the precursor protein of AngII and angioten- 745
682 and 3 and of genes and proteins critical for mitochondrial sinogen125 as well as aldosterone synthase.75 Indeed, 746
683 biogenesis.106 Similarly, their urine exosomes have plasma aldosterone is independently associated with 747
684 748
685
decreased mitochondrial DNA.106 NOX4-derived ROS obesity.126 A 5% weight loss in obese women reduces 749
686 decrease mitochondrial function in endothelial cells via renin-angiotensin-aldosterone activity in both adipose 750
687 disruption of the electron transport chain I107 and causes tissue and plasma.127 In addition, increased visceral 751
688 extracellular matrix protein accumulation in mesangial and retroperitoneal fat may boost hypertension by com- 752
689 cells.108,109 Interestingly, these changes are associated pressing the kidneys. The intraabdominal pressure in 753
690 754
691
with AMPK inactivation108 and its activation reduced obese patients can be double that of normal sub- 755
692 renal fibrogenesis.109 A key pathway by which AMPK jects,128,129 and excessive fat accumulation in and 756
693 stimulation protects cells in a calorie-deprived state is around the kidneys is associated with increased 757
694 by stimulating the master regulator of mitochondrial intrarenal pressures, impaired pressure natriuresis, and 758
695 biogenesis, PPAR-g coactivator-1a.110 AMPK also in- hypertension.130 759
696 760
697
hibits activity of mammalian target of rapamycin, which In addition to the effects of fat, high serum insulin level 761
698 mediates NOX4-induced podocyte injury,111,112 thereby is associated with an increase in circulating levels of the 762
699 preventing kidney damage progression.113,114 potent vasoconstrictor endothelin-1 in healthy and IR in- 763
700 Furthermore, AngII not only increases mitochondrial dividuals.131 Endothelin-1 receptor antagonism effec- 764
701 production of ROS,115 but may also promote mitochon- tively reduced blood pressure in animal models of IR 765
702 766
703
drial degradation through the AT1-receptor, and suppress and hypertension,132 implicating endothelin-1 in their 767
their biogenesis through the AT2-receptor.116,117 pathogenesis. Furthermore, when coexisting with

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768 832
769 Metabolic Syndrome 833
770 834
771 835
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773 837
774 838
Insulin Oxidative Stress, Adipose tissue
775 839
resistance inflammation expansion
776 840
777 841
778 842
779 843
780 Endothelial Renin-angiotensin- Adipokine 844
dysfunction aldosterone activation imbalance
781 845
782 846
783 847
784 Mitochondrial 848
785 dysfuntion 849
Hypertension Albuminuria
786 850
787 851
788 852
789 853
790 854
791 855
Microvascular Tubulointerstitial
792 Podocyte injury
fibrosis
856
remodeling
793 857
794 858
795 859
796 860
797 861
798 862
799 Renal Damage 863
800 864
801 865
Fig 2. ---.
802 866
803 867
804 868
hyperglycemia, insulin exhibits antinatriuretic effect by which leads to hyperuricemia, enabled observing a
805 869
806 promoting sodium retention.133 As proximal tubular direct relationship between blood pressure and UA. In 870
807 epithelial cells often undergo hypertrophy in obese sub- mice, blood pressure increases by 10-mm Hg for each 871
808 jects,134 together they may account for increased sodium 0.03-mmol/L (0.5-mg/dL) incremental rise in serum 872
809 reabsorption and elevation of arterial pressure. As dis- UA.143 Allopurinol, an UA lowering drug, prophylacti- 873
810 874
cussed earlier, increased leptin and reduced adiponectin cally prevented hyperinsulinemia, systolic hyperten-
811 875
812 in obesity may also increase sympathetic nerve activ- sion, and hypertriglyceridemia.140 In rat kidneys, 876
813 ity,135,136 thus contributing to hypertension. hyperuricemia increased juxtaglomerular renin and 877
814 downregulated macula densa neuronal NO synthase.143 878
815 In vitro, UA inhibited NO production in endothelial 879
816 URIC ACID (UA) 880
cells,144 and dose-dependently inhibited endothelial
817 Hyperuricemia is commonly observed and strongly 881
818 vasodilatory response to acetylcholine,140 which may 882
819
associated with MetS. The prevalence of MetS in turn compromise blood and oxygen supply to the kid- 883
820 increased from 5.9% for UA levels under 6 mg/dL to ney. Evidently, decreasing UA levels may have benefi- 884
821 59.0% for levels 10 mg/dL or greater,137 and hyperuri- cial effects in MetS. 885
822 cemia correlates with elevated fasting insulin level.138 886
823 Moreover, based on a recent systemic review including 887
824 CONCLUSION 888
825
13 studies containing 190,718 participants, elevated 889
826 serum UA levels showed an increased risk for develop- Clearly, the impact of the MetS on the kidney is multi- 890
827 ment of chronic renal dysfunction.139 factorial. The current nutritional habits and lifestyles of 891
828 Animal studies have revealed that hyperuricemia many modern human subjects favor metabolic overload, 892
829 caused IR possibly due to the proinflammatory effect which underpins chronic metabolic diseases. The kid- 893
830 894
831
of UA on adipocytes140,141 and impairment of insulin- ney is a target organ susceptible to MetS (Fig 2); yet, 895
dependent glucose uptake.142 Using a uricase inhibitor, the appropriate treatment strategy for MetS-associated

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896 kidney disease remains to be identified. As MetS and not all component criteria contribute equally. Am J Transplant 960
897 type-2 diabetes share some common pathways (eg, hy- 2004;4:167583. 961
898 12. Danziger J. The bone-renal axis in early chronic kidney disease: 962
899
perfiltration, oxidative stress, etc.), MetS-associated an emerging paradigm. Nephrol Dial Transplant 2008;23: 963
900 kidney damage may resemble the early stage of diabetic 27337. 964
901 nephropathy and merits further studies. In addition to 13. Davies MR, Lund RJ, Mathew S, Hruska KA. Low turnover os- 965
902 screening, lifestyle modifications, and management of teodystrophy and vascular calcification are amenable to skeletal 966
903 MetS risk factors and CKD, target-specific therapeutic anabolism in an animal model of chronic kidney disease and the 967
904 metabolic syndrome. J Am Soc Nephrol 2005;16:91728. 968
905
interventions are in need and warrant investigation to 14. Lerman LO, Lerman A. The metabolic syndrome and early kid- 969
906 prevent the development and slow the progression of ney disease: another link in the chain? Rev Esp Cardiol 2011;64: 970
907 CKD in MetS. 35860. 971
908 15. Zhang X, Li ZL, Woollard JR, et al. Obesity-metabolic derange- 972
909 ment preserves hemodynamics but promotes intrarenal adiposity 973
ACKNOWLEDGMENT
910 and macrophage infiltration in swine renovascular disease. Am J 974
911 Conflicts of Interest: All authors have read the jour- Physiol Renal Physiol 2013;305:F26576. 975
912 nals policy on disclosure of potential conflicts of inter- 16. Mostbeck GH, Kain R, Mallek R, et al. Duplex Doppler sonog- 976
913 raphy in renal parenchymal disease. Histopathologic correlation. 977
est and have none to declare. All authors have read the
914 J Ultrasound Med 1991;10:18994. 978
915 journals authorship agreement and that the manuscript 17. Buscemi S, Verga S, Batsis JA, et al. Intra-renal hemodynamics 979
916 has been reviewed by and approved by all named au- and carotid intima-media thickness in the metabolic syndrome. 980
917 thors. Diabetes Res Clin Pract 2009;86:17785. 981
918 This work was partly supported by NIH Grants 18. Sanchez-Lozada LG, Tapia E, Jimenez A, et al. Fructose- 982
919 induced metabolic syndrome is associated with glomerular hy- 983
DK104273, DK102325, DK73608, DK100081, and
920 pertension and renal microvascular damage in rats. Am J Physiol 984
921 HL123160. Renal Physiol 2007;292:F4239. 985
922 19. Nakagawa T, Kang DH, Ohashi R, et al. Tubulointerstitial dis- 986
923 ease: role of ischemia and microvascular disease. Curr Opin 987
924 REFERENCES Nephrol Hypertens 2003;12:23341. 988
925 1. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and man- 20. Costa C, Incio J, Soares R. Angiogenesis and chronic inflamma- 989
926 agement of the metabolic syndrome: an American Heart Associ- tion: cause or consequence? Angiogenesis 2007;10:14966. 990
927 ation/National Heart, Lung, and Blood Institute Scientific 21. Chade AR, Hall JE. Role of the renal microcirculation in pro- 991
928 Statement. Circulation 2005;112:273552. gression of chronic kidney injury in obesity. Am J Nephrol 992
929 2. Alberti KG, Zimmet P, Shaw J. Metabolic syndromea new 2016;44:35467. 993
930 world-wide definition. A consensus statement from the Interna- 22. Li Z, Woollard JR, Wang S, et al. Increased glomerular filtration 994
931 tional Diabetes Federation. Diabet Med 2006;23:46980. rate in early metabolic syndrome is associated with renal 995
932 3. Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of adiposity and microvascular proliferation. Am J Physiol Renal 996
933 the metabolic syndrome in the United States, 2003-2012. Physiol 2011;301:F107887. 997
934 JAMA 2015;313:19734. 23. Li ZL, Woollard JR, Ebrahimi B, et al. Transition from obesity to 998
935 4. Luk AO, So WY, Ma RC, et al. Metabolic syndrome predicts new metabolic syndrome is associated with altered myocardial auto- 999
936 onset of chronic kidney disease in 5,829 patients with type 2 dia- phagy and apoptosis. Arterioscler Thromb Vasc Biol 2012;32: 1000
937 betes: a 5-year prospective analysis of the Hong Kong Diabetes 113241. 1001
938 Registry. Diabetes Care 2008;31:235761. 24. Kim YW, Byzova TV. Oxidative stress in angiogenesis and 1002
939 5. DeFina LF, Vega GL, Leonard D, Grundy SM. Fasting glucose, vascular disease. Blood 2014;123:62531. 1003
940 obesity, and metabolic syndrome as predictors of type 2 diabetes: 25. Hale LJ, Hurcombe J, Lay A, et al. Insulin directly stimulates 1004
941 the Cooper Center Longitudinal Study. J Investig Med 2012;60: VEGF-A production in the glomerular podocyte. Am J Physiol 1005
942 11648. Renal Physiol 2013;305:F1828. 1006
943 6. Hoehner CM, Greenlund KJ, Rith-Najarian S, Casper ML, 26. Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity- 1007
944 McClellan WM. Association of the insulin resistance syndrome induced hypertension: interaction of neurohumoral and renal 1008
945 and microalbuminuria among nondiabetic native Americans. The mechanisms. Circ Res 2015;116:9911006. 1009
946 Inter-Tribal Heart Project. J Am Soc Nephrol 2002;13:162634. 27. Cohen AJ, McCarthy DM, Stoff JS. Direct hemodynamic effect 1010
947 7. Locatelli F, Pozzoni P, Del Vecchio L. Renal manifestations in of insulin in the isolated perfused kidney. Am J Physiol 1989; 1011
948 the metabolic syndrome. J Am Soc Nephrol 2006;17:S815. 257:F5805. 1012
949 8. Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome 28. Hayashi K, Fujiwara K, Oka K, Nagahama T, Matsuda H, 1013
950 and chronic kidney disease in U.S. adults. Ann Intern Med Saruta T. Effects of insulin on rat renal microvessels: studies 1014
951 2004;140:16774. in the isolated perfused hydronephrotic kidney. Kidney Int 1015
952 9. Alexander MP, Patel TV, Farag YM, Florez A, Rennke HG, 1997;51:150713. 1016
953 Singh AK. Kidney pathological changes in metabolic syndrome: 29. Ter Maaten JC, Bakker SJ, Serne EH, Moshage HJ, Donker AJ, 1017
954 a cross-sectional study. Am J Kidney Dis 2009;53:7519. Gans RO. Insulin-mediated increases in renal plasma flow are 1018
955 10. Porrini E, Delgado P, Bigo C, et al. Impact of metabolic syn- impaired in insulin-resistant normal subjects. Eur J Clin Invest 1019
956 drome on graft function and survival after cadaveric renal trans- 2000;30:10908. 1020
957 plantation. Am J Kidney Dis 2006;48:13442. 30. Vicent D, Ilany J, Kondo T, et al. The role of endothelial insulin 1021
958 11. de Vries AP, Bakker SJ, van Son WJ, et al. Metabolic syndrome signaling in the regulation of vascular tone and insulin resis- 1022
959 is associated with impaired long-term renal allograft function; tance. J Clin Invest 2003;111:137380. 1023

REV 5.4.0 DTD
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22 December 2016
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 Translational Research
Volume - Zhang and Lerman 9

1024 31. Burlacu A, Siriopol D, Voroneanu L, et al. Atherosclerotic renal 49. Chen J, Muntner P, Hamm LL, et al. Insulin resistance and risk of 1088
1025 artery stenosis prevalence and correlations in acute myocardial chronic kidney disease in nondiabetic US adults. J Am Soc 1089
1026 infarction patients undergoing primary percutaneous coronary Nephrol 2003;14:46977. 1090
1027 interventions: data from nonrandomized single-center study 50. Groop PH, Forsblom C, Thomas MC. Mechanisms of disease: 1091
1028 (REN-ACS)-A single center, prospective, observational study. pathway-selective insulin resistance and microvascular compli- 1092
1029 J Am Heart Assoc 2015;4:e002379. cations of diabetes. Nat Clin Pract Endocrinol Metab 2005;1: 1093
1030 32. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. 10010. 1094
1031 J Clin Invest 2005;115:11119. 51. Nestler JE, Barlascini CO, Tetrault GA, Fratkin MJ, Clore JN, 1095
1032 33. Sur G, Floca E, Kudor-Szabadi L, Sur ML, Sur D, Samasca G. Blackard WG. Increased transcapillary escape rate of albumin 1096
1033 The relevance of inflammatory markers in metabolic syndrome. in nondiabetic men in response to hyperinsulinemia. Diabetes 1097
1034 Maedica (Buchar) 2014;9:158. 1990;39:12127. 1098
1035 34. Hotamisligil GS. Inflammation and metabolic disorders. Nature 52. Jheng HF, Tsai PJ, Chuang YL, et al. Albumin stimulates renal 1099
1036 2006;444:8607. tubular inflammation through an HSP70-TLR4 axis in mice 1100
1037 35. Dominguez J, Wu P, Packer CS, Temm C, Kelly KJ. Lipotoxic with early diabetic nephropathy. Dis Model Mech 2015;8: 1101
1038 and inflammatory phenotypes in rats with uncontrolled meta- 131121. 1102
1039 bolic syndrome and nephropathy. Am J Physiol Renal Physiol 53. Butlen D, Vadrot S, Roseau S, Morel F. Insulin receptors along 1103
1040 2007;293:F6709. the rat nephron: [125I] insulin binding in microdissected 1104
1041 36. Al-Shanti N, Stewart CE. Inhibitory effects of IL-6 on IGF-1 ac- glomeruli and tubules. Pflugers Arch 1988;412:60412. 1105
1042 tivity in skeletal myoblasts could be mediated by the activation 54. Nakamura R, Emmanouel DS, Katz AI. Insulin binding sites in 1106
1043 of SOCS-3. J Cell Biochem 2012;113:92333. various segments of the rabbit nephron. J Clin Invest 1983;72: 1107
1044 37. De Benedetti F, Meazza C, Oliveri M, et al. Effect of IL-6 on IGF 38892. 1108
1045 binding protein-3: a study in IL-6 transgenic mice and in patients 55. Mima A, Ohshiro Y, Kitada M, et al. Glomerular-specific protein 1109
1046 with systemic juvenile idiopathic arthritis. Endocrinology 2001; kinase C-beta-induced insulin receptor substrate-1 dysfunction 1110
1047 142:481826. and insulin resistance in rat models of diabetes and obesity. Kid- 1111
1048 38. Bahceci M, Gokalp D, Bahceci S, Tuzcu A, Atmaca S, Arikan S. ney Int 2011;79:88396. 1112
1049 The correlation between adiposity and adiponectin, tumor necro- 56. Kim EY, Dryer SE. Effects of insulin and high glucose on mobi- 1113
1050 sis factor alpha, interleukin-6 and high sensitivity C-reactive lization of slo1 BKCa channels in podocytes. J Cell Physiol 1114
1051 protein levels. Is adipocyte size associated with inflammation 2011;226:230715. 1115
1052 in adults? J Endocrinol Invest 2007;30:2104. 57. Kim EY, Anderson M, Dryer SE. Insulin increases surface 1116
1053 39. Ma S, Zhu XY, Eirin A, et al. Perirenal fat promotes renal arterial expression of TRPC6 channels in podocytes: role of NADPH ox- 1117
1054 endothelial dysfunction in obese swine through tumor necrosis idases and reactive oxygen species. Am J Physiol Renal Physiol 1118
1055 factor-alpha. J Urol 2016;195:11529. 2012;302:F298307. 1119
1056 40. Forsythe LK, Wallace JM, Livingstone MB. Obesity and inflam- 58. Wang S, Denichilo M, Brubaker C, Hirschberg R. Connective 1120
1057 mation: the effects of weight loss. Nutr Res Rev 2008;21: tissue growth factor in tubulointerstitial injury of diabetic ne- 1121
1058 11733. phropathy. Kidney Int 2001;60:96105. 1122
1059 41. Abd El-Kader MS, Al-Jiffri O, Ashmawy EM. Impact of weight 59. Namikoshi T, Tomita N, Satoh M, et al. Pioglitazone enhances 1123
1060 loss on markers of systemic inflammation in obese Saudi chil- the antihypertensive and renoprotective effects of candesartan 1124
1061 dren with asthma. Afr Health Sci 2013;13:6828. in Zucker obese rats fed a high-protein diet. Hypertens Res 1125
1062 42. Friedman JE, Dohm GL, Elton CW, et al. Muscle insulin 2008;31:74555. 1126
1063 resistance in uremic humans: glucose transport, glucose trans- 60. Busch M, Franke S, Ruster C, Wolf G. Advanced glycation end- 1127
1064 porters, and insulin receptors. Am J Physiol 1991;261: products and the kidney. Eur J Clin Invest 2010;40:74255. 1128
1065 E8794. 61. Ruster C, Wolf G. Adipokines promote chronic kidney disease. 1129
1066 43. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin- Nephrol Dial Transplant 2013;28 Suppl 4:iv814. 1130
1067 interacting protein links oxidative stress to inflammasome acti- 62. Miyamoto S, Sharma K. Adipokines protecting CKD. Nephrol 1131
1068 vation. Nat Immunol 2010;11:13640. Dial Transplant 2013;28 Suppl 4:iv1522. 1132
1069 44. Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, 63. Sharma K. The link between obesity and albuminuria: adiponec- 1133
1070 Shoelson SE. The effects of salsalate on glycemic control in pa- tin and podocyte dysfunction. Kidney Int 2009;76:1458. 1134
1071 tients with type 2 diabetes: a randomized trial. Ann Intern Med 64. Sharma K, Ramachandrarao S, Qiu G, et al. Adiponectin regu- 1135
1072 2010;152:34657. lates albuminuria and podocyte function in mice. J Clin Invest 1136
1073 45. Goldfine AB, Silver R, Aldhahi W, et al. Use of salsalate to target 2008;118:164556. 1137
1074 inflammation in the treatment of insulin resistance and type 2 65. Rutkowski JM, Wang ZV, Park AS, et al. Adiponectin promotes 1138
1075 diabetes. Clin Transl Sci 2008;1:3643. functional recovery after podocyte ablation. J Am Soc Nephrol 1139
1076 46. Stanley TL, Zanni MV, Johnsen S, et al. TNF-alpha antagonism 2013;24:26882. 1140
1077 with etanercept decreases glucose and increases the proportion 66. Lee MP, Orlov D, Sweeney G. Leptin induces rat glomerular me- 1141
1078 of high molecular weight adiponectin in obese subjects with fea- sangial cell hypertrophy, but does not regulate hyperplasia or 1142
1079 tures of the metabolic syndrome. J Clin Endocrinol Metab 2011; apoptosis. Int J Obes (Lond) 2005;29:1395401. 1143
1080 96:E14650. 67. Chen KH, Hung CC, Hsu HH, Jing YH, Yang CW, Chen JK. Re- 1144
1081 47. De Cosmo S, Menzaghi C, Prudente S, Trischitta V. Role of in- sveratrol ameliorates early diabetic nephropathy associated with 1145
1082 sulin resistance in kidney dysfunction: insights into the mecha- suppression of augmented TGF-beta/smad and ERK1/2 1146
1083 nism and epidemiological evidence. Nephrol Dial Transplant signaling in streptozotocin-induced diabetic rats. Chem Biol 1147
1084 2013;28:2936. Interact 2011;190:4553. 1148
1085 48. Kurella M, Lo JC, Chertow GM. Metabolic syndrome and the 68. Kumpers P, Gueler F, Rong S, et al. Leptin is a coactivator of 1149
1086 risk for chronic kidney disease among nondiabetic adults. J TGF-beta in unilateral ureteral obstructive kidney disease. Am 1150
1087 Am Soc Nephrol 2005;16:213440. J Physiol Renal Physiol 2007;293:F135562. 1151

REV 5.4.0 DTD
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22 December 2016
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 Translational Research
10 Zhang and Lerman - 2016

1152 69. Kusminski CM, McTernan PG, Kumar S. Role of resistin in 89. Whaley-Connell A, Habibi J, Nistala R, et al. Attenuation of 1216
1153 obesity, insulin resistance and Type II diabetes. Clin Sci NADPH oxidase activation and glomerular filtration barrier re- 1217
1154 (Lond) 2005;109:24356. modeling with statin treatment. Hypertension 2008;51:47480. 1218
1155 70. Menzaghi C, Salvemini L, Fini G, et al. Serum resistin and kid- 90. Block K, Eid A, Griendling KK, Lee DY, Wittrant Y, Gorin Y. 1219
1156 ney function: a family-based study in non-diabetic, untreated in- Nox4 NAD(P)H oxidase mediates Src-dependent tyrosine phos- 1220
1157 dividuals. PLoS One 2012;7:e38414. phorylation of PDK-1 in response to angiotensin II: role in me- 1221
1158 71. Axelsson J, Bergsten A, Qureshi AR, et al. Elevated resistin sangial cell hypertrophy and fibronectin expression. J Biol Chem 1222
1159 levels in chronic kidney disease are associated with decreased 2008;283:2406176. 1223
1160 glomerular filtration rate and inflammation, but not with insulin 91. Block K, Gorin Y, Abboud HE. Subcellular localization of Nox4 1224
1161 resistance. Kidney Int 2006;69:596604. and regulation in diabetes. Proc Natl Acad Sci U S A 2009;106: 1225
1162 72. Habeeballah H, Alsuhaymi N, Stebbing MJ, Jenkins TA, 1438590. 1226
1163 Badoer E. Central leptin and resistin combined elicit enhanced 92. Wingler K, Wunsch S, Kreutz R, Rothermund L, Paul M, 1227
1164 central effects on renal sympathetic nerve activity. Exp Physiol Schmidt HH. Upregulation of the vascular NAD(P)H-oxidase 1228
1165 2016;101:791800. isoforms Nox1 and Nox4 by the renin-angiotensin system 1229
1166 73. Kosari S, Rathner JA, Badoer E. Central resistin enhances renal in vitro and in vivo. Free Radic Biol Med 2001;31:145664. 1230
1167 sympathetic nerve activity via phosphatidylinositol 3-kinase but 93. Bondi CD, Manickam N, Lee DY, et al. NAD(P)H oxidase me- 1231
1168 reduces the activity to brown adipose tissue via extracellular diates TGF-beta1-induced activation of kidney myofibroblasts. 1232
1169 signal-regulated kinase 1/2. J Neuroendocrinol 2012;24:14329. J Am Soc Nephrol 2010;21:93102. 1233
1170 74. Hall JE, Brands MW, Dixon WN, Smith MJ Jr. Obesity-induced 94. Nunnari J, Suomalainen A. Mitochondria: in sickness and in 1234
1171 hypertension. Renal function and systemic hemodynamics. Hy- health. Cell 2012;148:114559. 1235
1172 pertension 1993;22:2929. 95. Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and 1236
1173 75. Briones AM, Nguyen Dinh Cat A, Callera GE, et al. Adipocytes therapeutics. Annu Rev Pathol 2010;5:297348. 1237
1174 produce aldosterone through calcineurin-dependent signaling 96. Duchen MR, Szabadkai G. Roles of mitochondria in human dis- 1238
1175 pathways: implications in diabetes mellitus-associated obesity ease. Essays Biochem 2010;47:11537. 1239
1176 and vascular dysfunction. Hypertension 2012;59:106978. 97. Brand MD, Murphy MP. Control of electron flux through the res- 1240
1177 76. Fujita T. Aldosterone in salt-sensitive hypertension and meta- piratory chain in mitochondria and cells. Biol Rev Camb Philos 1241
1178 bolic syndrome. J Mol Med (Berl) 2008;86:72934. Soc 1987;62:14193. 1242
1179 77. Kriz W, Elger M, Mundel P, Lemley KV. Structure-stabilizing 98. Brown GC. Control of respiration and ATP synthesis in mamma- 1243
1180 forces in the glomerular tuft. J Am Soc Nephrol 1995;5:17319. lian mitochondria and cells. Biochem J 1992;284:113. 1244
1181 78. Chen HM, Liu ZH, Zeng CH, Li SJ, Wang QW, Li LS. Podocyte 99. Eirin A, Lerman A, Lerman LO. The emerging role of mitochon- 1245
1182 lesions in patients with obesity-related glomerulopathy. Am J drial targeting in kidney disease. Handb Exp Pharmacol 2016. Q3 1246
1183 Kidney Dis 2006;48:7729. 100. Eirin A, Lerman A, Lerman LO. Mitochondria: a pathogenic 1247
1184 79. Wiggins JE, Goyal M, Sanden SK, et al. Podocyte hypertrophy, paradigm in hypertensive renal disease. Hypertension 2015;65: 1248
1185 adaptation, and decompensation associated with glomer- 26470. 1249
1186 ular enlargement and glomerulosclerosis in the aging rat: preven- 101. Granata S, Dalla Gassa A, Tomei P, Lupo A, Zaza G. Mitochon- 1250
1187 tion by calorie restriction. J Am Soc Nephrol 2005;16:295366. dria: a new therapeutic target in chronic kidney disease. Nutr 1251
1188 80. Kriz W, Hosser H, Hahnel B, Gretz N, Provoost AP. From Metab (Lond) 2015;12:49. 1252
1189 segmental glomerulosclerosis to total nephron degeneration 102. Lovisa S, Zeisberg M, Kalluri R. Partial epithelial-to- 1253
1190 and interstitial fibrosis: a histopathological study in rat models mesenchymal transition and other new mechanisms of kidney 1254
1191 and human glomerulopathies. Nephrol Dial Transplant 1998; fibrosis. Trends Endocrinol Metab 2016;27:68195. 1255
1192 13:278198. 103. Bonnard C, Durand A, Peyrol S, et al. Mitochondrial 1256
1193 81. Fukuda A, Chowdhury MA, Venkatareddy MP, et al. Growth- dysfunction results from oxidative stress in the skeletal mus- 1257
1194 dependent podocyte failure causes glomerulosclerosis. J Am cle of diet-induced insulin-resistant mice. J Clin Invest 2008; 1258
1195 Soc Nephrol 2012;23:135163. 118:789800. 1259
1196 82. Kambham N, Markowitz GS, Valeri AM, Lin J, DAgati VD. 104. Takabe W, Li R, Ai L, Yu F, Berliner JA, Hsiai TK. Oxidized 1260
1197 Obesity-related glomerulopathy: an emerging epidemic. Kidney low-density lipoprotein-activated c-Jun NH2-terminal kinase 1261
1198 Int 2001;59:1498509. regulates manganese superoxide dismutase ubiquitination: 1262
1199 83. DAgati VD, Chagnac A, de Vries AP, et al. Obesity-related glo- implication for mitochondrial redox status and apoptosis. Arte- 1263
1200 merulopathy: clinical and pathologic characteristics and patho- rioscler Thromb Vasc Biol 2010;30:43641. 1264
1201 genesis. Nat Rev Nephrol 2016;12:45371. 105. Pandey D, Bhunia A, Oh YJ, et al. OxLDL triggers retrograde 1265
1202 84. Fortuno A, San Jose G, Moreno MU, Beloqui O, Diez J, Zalba G. translocation of arginase2 in aortic endothelial cells via ROCK 1266
1203 Phagocytic NADPH oxidase overactivity underlies oxidative and mitochondrial processing peptidase. Circ Res 2014;115: 1267
1204 stress in metabolic syndrome. Diabetes 2006;55:20915. 4509. 1268
1205 85. Huang PL. Unraveling the links between diabetes, obesity, and 106. Sharma K, Karl B, Mathew AV, et al. Metabolomics reveals 1269
1206 cardiovascular disease. Circ Res 2005;96:112931. signature of mitochondrial dysfunction in diabetic kidney dis- 1270
1207 86. Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative ease. J Am Soc Nephrol 2013;24:190112. 1271
1208 stress in obesity and its impact on metabolic syndrome. J Clin 107. Koziel R, Pircher H, Kratochwil M, et al. Mitochondrial respira- 1272
1209 Invest 2004;114:175261. tory chain complex I is inactivated by NADPH oxidase Nox4. 1273
1210 87. Geiszt M, Kopp JB, Varnai P, Leto TL. Identification of renox, an Biochem J 2013;452:2319. 1274
1211 NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A 2000;97: 108. Papadimitriou A, Peixoto EB, Silva KC, Lopes de Faria JM, 1275
1212 80104. Lopes de Faria JB. Inactivation of AMPK mediates high 1276
1213 88. Eid AA, Gorin Y, Fagg BM, et al. Mechanisms of podocyte phosphate-induced extracellular matrix accumulation via 1277
1214 injury in diabetes: role of cytochrome P450 and NADPH oxi- NOX4/TGFss-1 signaling in human mesangial cells. Cell Phys- 1278
1215 dases. Diabetes 2009;58:120111. iol Biochem 2014;34:126072. 1279

REV 5.4.0 DTD
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22 December 2016
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Volume - Zhang and Lerman 11

1280 109. Eid AA, Lee DY, Roman LJ, Khazim K, Gorin Y. Sestrin 2 and ship to cardiorenal and metabolic disease. Hypertension 2015; 1344
1281 AMPK connect hyperglycemia to Nox4-dependent endothelial 65:4553. 1345
1282 nitric oxide synthase uncoupling and matrix protein expression. 127. Engeli S, Bohnke J, Gorzelniak K, et al. Weight loss and the 1346
1283 Mol Cell Biol 2013;33:343960. renin-angiotensin-aldosterone system. Hypertension 2005;45: 1347
1284 110. Dugan LL, You YH, Ali SS, et al. AMPK dysregulation pro- 35662. 1348
1285 motes diabetes-related reduction of superoxide and mitochon- 128. Sugerman H, Windsor A, Bessos M, Wolfe L. Intra-abdominal 1349
1286 drial function. J Clin Invest 2013;123:488899. pressure, sagittal abdominal diameter and obesity comorbidity. 1350
1287 111. Eid AA, Ford BM, Bhandary B, et al. Mammalian target of rapa- J Intern Med 1997;241:719. 1351
1288 mycin regulates Nox4-mediated podocyte depletion in diabetic 129. Cobb WS, Burns JM, Kercher KW, Matthews BD, James 1352
1289 renal injury. Diabetes 2013;62:293547. Norton H, Todd Heniford B. Normal intra-abdominal pressure 1353
1290 112. Eid AA, Ford BM, Block K, et al. AMP-activated protein kinase in healthy adults. J Surg Res 2005;129:2315. 1354
1291 (AMPK) negatively regulates Nox4-dependent activation of p53 130. Hall ME, do Carmo JM, da Silva AA, Juncos LA, Wang Z, 1355
1292 and epithelial cell apoptosis in diabetes. J Biol Chem 2010;285: Hall JE. Obesity, hypertension, and chronic kidney disease. Int 1356
1293 3750312. J Nephrol Renovasc Dis 2014;7:7588. 1357
1294 113. Godel M, Hartleben B, Herbach N, et al. Role of mTOR in po- 131. Sarafidis PA, Bakris GL. Review: insulin and endothelin: an 1358
1295 docyte function and diabetic nephropathy in humans and mice. interplay contributing to hypertension development? J Clin En- 1359
1296 J Clin Invest 2011;121:2197209. docrinol Metab 2007;92:37985. 1360
1297 114. Sharma K. Obesity, oxidative stress, and fibrosis in chronic kid- 132. Miller AW, Tulbert C, Puskar M, Busija DW. Enhanced endothe- 1361
1298 ney disease. Kidney Int Suppl (2011) 2014;4:1137. lin activity prevents vasodilation to insulin in insulin resistance. 1362
1299 115. Dikalov SI, Nazarewicz RR. Angiotensin II-induced production Hypertension 2002;40:7882. 1363
1300 of mitochondrial reactive oxygen species: potential mechanisms 133. Brands MW, Manhiani MM. Sodium-retaining effect of insulin 1364
1301 and relevance for cardiovascular disease. Antioxid Redox Signal in diabetes. Am J Physiol Regul Integr Comp Physiol 2012; 1365
1302 2013;19:108594. 303:R11019. 1366
1303 116. Mitsuishi M, Miyashita K, Muraki A, Itoh H. Angiotensin II re- 134. Tobar A, Ori Y, Benchetrit S, et al. Proximal tubular hyper- 1367
1304 duces mitochondrial content in skeletal muscle and affects gly- trophy and enlarged glomerular and proximal tubular urinary 1368
1305 cemic control. Diabetes 2009;58:7107. space in obese subjects with proteinuria. PLoS One 2013;8: 1369
1306 117. Abadir PM, Foster DB, Crow M, et al. Identification and charac- e75547. 1370
1307 terization of a functional mitochondrial angiotensin system. Proc 135. Ohashi K, Kihara S, Ouchi N, et al. Adiponectin replenishment 1371
1308 Natl Acad Sci U S A 2011;108:1484954. ameliorates obesity-related hypertension. Hypertension 2006; 1372
1309 118. Hoehn KL, Salmon AB, Hohnen-Behrens C, et al. Insulin resis- 47:110816. 1373
1310 tance is a cellular antioxidant defense mechanism. Proc Natl 136. Carlyle M, Jones OB, Kuo JJ, Hall JE. Chronic cardiovascular 1374
1311 Acad Sci U S A 2009;106:1778792. and renal actions of leptin: role of adrenergic activity. Hyperten- 1375
1312 119. Lee HK, Song JH, Shin CS, et al. Decreased mitochondrial DNA sion 2002;39:496501. 1376
1313 content in peripheral blood precedes the development of non- 137. Choi HK, Ford ES. Prevalence of the metabolic syndrome in in- 1377
1314 insulin-dependent diabetes mellitus. Diabetes Res Clin Pract dividuals with hyperuricemia. Am J Med 2007;120:4427. 1378
1315 1998;42:1617. 138. Yoo TW, Sung KC, Shin HS, et al. Relationship between serum 1379
1316 120. Fuku N, Park KS, Yamada Y, et al. Mitochondrial haplogroup uric acid concentration and insulin resistance and metabolic syn- 1380
1317 N9a confers resistance against type 2 diabetes in Asians. Am J drome. Circ J 2005;69:92833. 1381
1318 Hum Genet 2007;80:40715. 139. Li L, Yang C, Zhao Y, Zeng X, Liu F, Fu P. Is hyperuricemia an 1382
1319 121. Zhu C, Huang S, Yuan Y, et al. Mitochondrial dysfunction medi- independent risk factor for new-onset chronic kidney disease?: A 1383
1320 ates aldosterone-induced podocyte damage: a therapeutic target systematic review and meta-analysis based on observational 1384
1321 of PPARgamma. Am J Pathol 2011;178:202031. cohort studies. BMC Nephrol 2014;15:122. 1385
1322 122. Eirin A, Ebrahimi B, Kwon SH, et al. Restoration of mitochon- 140. Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid 1386
1323 drial cardiolipin attenuates cardiac damage in swine renovas- in fructose-induced metabolic syndrome. Am J Physiol Renal 1387
1324 cular hypertension. J Am Heart Assoc 2016;5. Physiol 2006;290:F62531. 1388
1325 123. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors 141. Baldwin W, McRae S, Marek G, et al. Hyperuricemia as a medi- 1389
1326 of blood pressure control in diverse North American settings: the ator of the proinflammatory endocrine imbalance in the adipose 1390
1327 antihypertensive and lipid-lowering treatment to prevent heart tissue in a murine model of the metabolic syndrome. Diabetes 1391
1328 attack trial (ALLHAT). J Clin Hypertens (Greenwich) 2002;4: 2011;60:125869. 1392
1329 393404. 142. Zhi L, Yuzhang Z, Tianliang H, Hisatome I, Yamamoto T, 1393
1330 124. Armitage JA, Burke SL, Prior LJ, et al. Rapid onset of renal sym- Jidong C. High uric acid induces insulin resistance in cardi- 1394
1331 pathetic nerve activation in rabbits fed a high-fat diet. Hyperten- omyocytes in vitro and in vivo. PLoS One 2016;11: 1395
1332 sion 2012;60:16371. e0147737. 1396
1333 125. Yvan-Charvet L, Quignard-Boulange A. Role of adipose tissue 143. Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid in- 1397
1334 renin-angiotensin system in metabolic and inflammatory dis- creases blood pressure in the rat by a novel crystal- 1398
1335 eases associated with obesity. Kidney Int 2011;79:1628. independent mechanism. Hypertension 2001;38:11016. 1399
1336 126. Buglioni A, Cannone V, Cataliotti A, et al. Circulating aldoste- 144. Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces 1400
1337 rone and natriuretic peptides in the general community: relation- endothelial dysfunction. Kidney Int 2005;67:173942. 1401
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1340 1404
1341 1405
1342 1406
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