Reactive Oxygen Species-Regulated Signaling Pathways in Diabetic Nephropathy

Lee, Hi Bahl; Yu, Mi Ra; Yang, Yanqiang; Jiang, Zongpei; Ha, Hunjoo

doi:10.1097/01.asn.0000077410.66390.0f

Cited by 426 publications

(336 citation statements)

References 37 publications

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“…18,19 Both hyperglycemia 20 and activation of the renin-angiotensin system 21 play a role in the generation of reactive oxygen species (ROS). Observations highlight the relevance of mitochondrial oxidative stress in diabetic vascular complications.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production

Prabhakar¹,

Starnes²,

Shi³

et al. 2007

Journal of the American Society of Nephrology

183

144

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The pathogenesis of diabetic nephropathy remains far from clear, partly due to the lack of a suitable animal model that mimics human renal disease in type 2 diabetes. In this study, the natural history of renal manifestations in ZSF 1 rats, a recently developed rodent model of type 2 diabetes, is described. Male ZSF 1 rats developed obesity and hyperglycemia by 20 weeks of age on a highcarbohydrate diet. They also developed systolic and diastolic hypertension, hypercholesterolemia, profound hypertriglyceridemia, proteinuria, and renal failure. Renal histology demonstrated changes consistent with early diabetic nephropathy, including arteriolar thickening, tubular dilation and atrophy, glomerular basement membrane thickening, and mesangial expansion. Furthermore, renal nitric oxide production was decreased, and homogenates from renal cortices demonstrated reduced expression of renal endothelial and inducible nitric oxide synthases. These changes were associated with increased urinary levels and renal expression of 8-hydroxydeoxyguanosine, an indicator of mitochondrial oxidative stress, as well as with increased renal peroxynitrite formation. Administration of either insulin or the antioxidant alpha-lipoic acid decreased proteinuria and oxidative stress, but only the former slowed progression of renal failure. We conclude that ZSF 1 rats represent the best available rat model to study nephropathy from type 2 diabetes and that the renal lesions are associated with increased oxidative stress and decreased renal nitric oxide availability. 18: 294518: -295218: , 200718: . doi: 10.1681 Despite several recent advances, the pathogenesis of diabetic nephropathy (DN) remains far from clear. 1 The lack of suitable diabetic animal models that develop nephropathy akin to human disease is a major barrier for progress in this field. Notwithstanding the contribution to mechanistic pathways, the in vitro models to study DN have compounded the problem, necessitating more dependable in vivo animal models. Furthermore, the growing epidemic of metabolic syndrome warrants need for animal models that develop hyperlipidemia and obesity in addition to maturity-onset diabetes to mimic complications of human diabetes and metabolic syndrome. We report here a genetically engineered rat that developed features of DN as well as full-blown metabolic syndrome. Furthermore, decreased renal nitric oxide (NO) production was noted in these rats, consistent with our previous observations in mesangial cell cultures in vitro that were exposed to high ambient glucose concentrations. These changes were associated with increased oxidative stress, which partly accounted for decreased NO levels. J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production

Prabhakar¹,

Starnes²,

Shi³

et al. 2007

Journal of the American Society of Nephrology

183

144

View full text Add to dashboard Cite

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“…Early effects of hyperglycemia are 1) activation of protein kinase C and 2) production of glucoxidative products such as Amadori and advance glycated end products (21) that lead to formation of reactive oxygen species (ROS). The accumulation of ROS in renal tissue in turn activates several signaling pathways associated with fibrogenesis (36).…”

Section: Discussionmentioning

confidence: 99%

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

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Tack I, Girolami J-P. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. Am J Physiol Renal Physiol 293: F1083-F1092, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00401.2006 is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-␤1 (TGF-␤-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-␤-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.angiotensin-converting enzyme inhibitor; oxidative stress; glutathione peroxidase activity; diabetes DIABETIC NEPHROPATHY (DN) causes the majority of end-stage renal diseases throughout the world (54). It was initially believed that elevated blood glucose was the major cause of renal damage in both type 1 and 2 diabetes. However, several clinical studies have demonstrated that strict glycemic control is not sufficient to prevent the progression of renal dysfunction and the development of glomerular lesions. The mechanisms underlying the progression of diabetic kidney disease are intricate and still not completely understood. Among the many pathophysiological mechanisms possible, several growth factors and cytokines have been put forward to account for the onset of DN. This is particularly the case for the paracrine expression of insulin-like growth factor-1 (IGF-1), transforming growth factor-␤ (TGF-␤) (20), and platelet-derived growth factor (PDG...

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“…Activation of the NAD(P)H oxidase system requires the participation of p47 phox , one of the NAD(P)H oxidase subunits, which plays a central role in the scenario of NAD(P)H oxidase activation (10). Activation of nuclear factor-kappa B (NF-κB) is involved in the expression of pro-inflammatory genes (11).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II stimulates MCP-1 production in rat glomerular endothelial cells via NAD(P)H oxidase-dependent nuclear factor-kappa B signaling

Pan

Yang

Cheng

2009

Braz J Med Biol Res

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Angiotensin II (Ang II) plays a crucial role in the pathogenesis of renal diseases. The objective of the present study was to investigate the possible inflammatory effect of Ang II on glomerular endothelial cells and the underlying mechanism. We isolated and characterized primary cultures of rat glomerular endothelial cells (GECs) and observed that Ang II induced the synthesis of monocyte chemoattractant protein-1 (MCP-1) in GECs as demonstrated by Western blot. Ang II stimulation, at concentrations ranging from 0.1 to 10 μm, of rat GECs induced a rapid increase in the generation of reactive oxygen species as indicated by laser fluoroscopy. The level of p47 phox protein, an NAD(P)H oxidase subunit, was also increased by Ang II treatment. These effects of Ang II on GECs were all reduced by diphenyleneiodonium (1.0 μm), an NAD(P)H oxidase inhibitor. Ang II stimulation also promoted the activation of nuclear factor-kappa B (NF-κB). Telmisartan (1.0 μm), an AT 1 receptor blocker, blocked all the effects of Ang II on rat GECs. These data suggest that the inhibition of NAD(P)H oxidase-dependent NF-κB signaling reduces the increase in MCP-1 production by GECs induced by Ang II. This may provide a mechanistic basis for the benefits of selective AT 1 blockade in dealing with chronic renal disease.

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Reactive Oxygen Species-Regulated Signaling Pathways in Diabetic Nephropathy

Cited by 426 publications

References 37 publications

Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production

Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Angiotensin II stimulates MCP-1 production in rat glomerular endothelial cells via NAD(P)H oxidase-dependent nuclear factor-kappa B signaling

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