Original ContributionAldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells
Introduction
Diabetes accounts for at least ∼35% of all new cases of end-stage renal disease in the United States [1], and diabetic patients make up the fastest growing group of renal dialysis and transplant recipients. The Diabetes Control and Complications Trial [2] and the U.K. Prospective Diabetes Study [3] strongly suggest the importance of hyperglycemia in the pathogenesis of chronic complications of diabetes mellitus including diabetic renal disease. Hyperglycemia leads to diabetic nephropathy (DN) via multiple mechanisms, and among them increased aldose reductase (AR) activity [4], [5], nonenzymatic glycation and glycooxidation [6], [7], activation of protein kinase C (PKC) and hexosamine pathway [8], [9], [10], arachidonic acid metabolism via 12/15-lipoxygenase pathway [11], [12], and triose phosphate accumulation [13] are the best studied. Growing evidence obtained in diabetic animals (primarily, STZ (streptozotocin)-diabetic rats and mice) [14], [15], [16], [17] as well as cell culture models [18], [19], [20] implicates free radicals and the potent oxidant peroxynitrite (a product of superoxide anion radical reaction with nitric oxide) in both hemodynamic and metabolic abnormalities leading to DN.
Oxidative stress affects all three compartments of the renal cortex, i.e., glomeruli [21], tubulo-interstitium [22], and vasculature [23]. Renal hydrogen peroxide overproduction and lipid peroxide accumulation occur at a very early stage of STZ-diabetes [24] and are associated with clearly manifest impairment of antioxidative defense and, in particular, GSH and ascorbate (AA) depletion, changes in glutathione and ascorbate redox states reflecting in increased oxidized glutathione(GSSG)/GSH and dehydroAA/AA ratios, and upregulated superoxide dismutase, GSH peroxidase, GSH transferase, and GSSG reductase activities [14], [25]. Enhanced lipid peroxidation and GSH depletion have also been documented in the model of advanced DN [15]. Evidence for the presence of peroxynitrite-induced injury in the diabetic kidney is emerging [17], [26].
Oxidative-nitrosative stress triggers several important downstream mechanisms, i.e., activation of mitogen-activated protein kinases [20], [27], the nuclear transcription factor NF-κB [28], [29], and upregulation of growth factors such as transforming growth factor-β (TGF-β) [14], [15], cytokines [30], [31], and vascular endothelial growth factor [32] implicated in diabetic renal disease [12], [27], [28], [29], [33], [34]. In vitro and in vivo studies in nondiabetic models of oxidative injury as well as animal and cell culture models of diabetic complications revealed that free radical and peroxynitrite-induced DNA single-strand breakage is also responsible for activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and resultant energy failure, profound metabolic imbalances, and changes in transcriptional regulation and gene expression [35], [36], [37]. Recent studies including those from our group generated evidence of an important role of PARP activation in diabetic endothelial [38] and myocardial [39] dysfunction, peripheral neuropathy [40], [41], and retinopathy [42], [43]. We have also demonstrated (1) tubular PARP activation manifested by increased poly(ADP-ribose) immunoreactivity, and (2) the key role of PARP in upregulation of endothelin-1 and endothelin (A) and (B) receptors, known to play an important role in DN, in the renal cortex of STZ-diabetic rats with 4-week duration of diabetes [44].
The interactions among various hyperglycemia-initiated mechanisms are not completely understood, and the relation between increased AR activity and oxidative-nitrosative stress/PARP activation in the renal cortex has never been explored. The present study was designed to evaluate the effect of pharmacological AR inhibition with the potent and highly specific AR inhibitor (ARI) fidarestat [45], [46], [47] on nitrosative stress and PARP activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. Our animal studies performed in the STZ-diabetic rat model as well as in vitro studies in high-glucose-exposed human mesangial cells provide evidence of the major contribution of increased AR activity to diabetes- and hyperglycemia-associated nitrosative stress and PARP activation in the renal cortex, and, specifically, the key cell target in DN, i.e., glomerular mesangial cells. Furthermore, they identify abundant AR protein expression and early high-glucose-induced peroxynitrite formation and PARP activation in human mesangial cells, thus suggesting the importance of these mechanisms in human DN.
Section snippets
Reagents
Unless otherwise stated, all chemicals were of reagent-grade quality, and were purchased from Sigma Chemical Co. (St. Louis, MO). Methanol (HPLC grade), perchloric acid, hydrochloric acid, and sodium hydroxide were obtained from Fisher Scientific (Pittsburgh, PA). Reagents for immunohistochemistry were purchased from Vector Laboratories, Inc., Burlingdale, CA and Dako Laboratories, Inc. (Santa Barbara, CA) as specified in the procedures. Monoclonal anti-nitrotyrosine (NT) antibody, clone 1A6
Results
The final body weights were comparably lower in untreated and fidarestat-treated diabetic rats than in the control group (Table 1). The final blood glucose concentrations were similarly elevated in untreated and fidarestat-treated diabetic rats compared with the control rats.
Kidney weights were increased in diabetic rats compared with controls (2.41 ± 0.059 vs 1.79 ± 0.061 g, p < 0.01), and this increase was slightly, but significantly, reduced by fidarestat (2.2 ± 0.088 g, p < 0.01 vs
Discussion
Our results provide evidence of clearly manifest nitrosative stress in early experimental DN. Increased immunoreactivity of NT (a marker of peroxynitrite-induced injury) in both glomerular and tubular compartments of the renal cortex of STZ-diabetic rats in the present study is consistent with elevated renal nitrosylated protein content (assessed by Western blot analysis) in another report [49]. Furthermore, increased NT immunoreactivity has also been documented in vasculature of diabetic rats
Acknowledgments
The study was supported by the National Institutes of Health Grant 1R21DK070720-01, grants from American Diabetes Association and Juvenile Diabetes Research Foundation (all to Irina G. Obrosova), and the Juvenile Diabetes Research Foundation Center for the Study of Complications of Diabetes Grant 4-200-421 (to I. G.Obrosova and M.J. Stevens). The authors are grateful to Drs. D. Carper, R.L. Sorenson, and J.M. Petrash for their gifts of AR antibodies, and human AR enzyme.
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2015, Drug Discovery TodayCitation Excerpt :In vivo, excessive accumulation of sorbitol and fructose in the renal cortex of STZ-induced diabetic rats was completely prevented by fidarestat treatment. In conclusion, fidarestat treatment, at least in part, counteracted nitrosative stress and polymerase activation by reducing nitrotyrosine and poly(ADP-ribose) concentrations in the diabetic renal cortex and prevented diabetes-induced increase in kidney weight, justifying new beneficial properties of fidarestat in experimental and, potentially, human DN [63]. Although a great deal of evidence indicates that AR and the polyol pathway represent a potential and promising therapeutic target for DN [64], the low tissue permeation of ARIs with carboxylic acid scaffold attributed to their low pKa values is the common problem that limits the bioavailability in vivo.
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2015, Pharmacological ReportsCitation Excerpt :This is confirmed by the finding that abnormal polyol pathway in diabetic rats resulted in glomerulopathy and renal hypofunction [3]. Notably, aldose reductase inhibitors exhibited protective effect on diabetic nephropathy possibly via counteracting oxidative and nitrosative stress in diabetic kidney [48] and/or reducing renal vascular endothelial growth factor VEGF overexpression [49]. Normalization of AR activity by NaHS is a key finding in this study.
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