Diabetic nephropathy: Important pathophysiologic mechanisms

Soldatos, Georgia; Cooper, Mark E.

doi:10.1016/j.diabres.2008.09.042

Cited by 104 publications

(73 citation statements)

References 42 publications

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“…Although the aetiology of Type I and Type II diabetes is notably distinct, glucose-evoked changes in renal physiology are almost indistinguishable and often lead to complete destruction of kidney function prompting the need for dialysis or transplantation therapy [2]. Multiple structural and functional changes are associated with the disease, specifically in the glomerulus, tubulointerstitium and vasculature [3], where glycaemic injury includes structural abnormalities ranging from hypertrophy, thickening of the glomerular basement membrane, tubular atrophy and interstitial fibrosis [4]. These changes contribute to increased glomerular filtration rate, proteinuria, systemic hypertension and the loss of renal function [4].…”

Section: Introductionmentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

173

187

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Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signaling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signaling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

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Section: Introductionmentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

173

187

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“…It is now well recognized that the pathogenesis of diabetic nephropathy is multifactorial. Over the last decade, diverse pathological mechanisms have been proposed to be involved in the onset and development of diabetic nephropathy, such as genetic and hemodynamic factors, oxidative stress and cytokine signaling (3,4). Nowadays, therapies for diabetic nephropathy have been limited to drugs that improve blood pressure or control blood glucose levels.…”

Section: Introductionmentioning

confidence: 99%

Autologous transplantation of adipose-derived mesenchymal stem cells ameliorates streptozotocin-induced diabetic nephropathy in rats by inhibiting oxidative stress, pro-inflammatory cytokines and the p38 MAPK signaling pathway

et al. 2012

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Abstract. Diabetic nephropathy is the leading cause of endstage renal disease. The aim of this study was to investigate the renoprotective effects of autologous transplantation of adiposederived mesenchymal stem cells (ADMSCs) and to delineate its underlying mechanisms of action in diabetic nephropathy. Diabetes was induced in adult male Sprague-Dawley rats by streptozotocin (STZ) injection. ADMSCs were administered intravenously 4 weeks after STZ injection and metabolic indices and renal structure were assessed (12 weeks). Markers of diabetes including blood glucose, cholesterol, triglycerides, urea nitrogen and creatinine were measured. Renal pathology, levels of oxidative stress and the expression of pro-inflammatory cytokines and the MAPK signaling pathway members were also determined. Autologous transplantation of ADMSCs significantly attenuated common metabolic disorder symptoms associated with diabetes. Furthermore, ADMSC administration minimized pathological alterations, reduced oxidative damage and suppressed the expression of pro-inflammatory cytokines in the renal tissues of diabetic rats. ADMSC transplantation also decreased the expression of p-p38, p-ERK and p-JNK, which are all important molecules of the MAPK signaling pathway. In conclusion, we provide experimental evidence demonstrating that autologous transplantation of ADMSCs can be used therapeutically to improve metabolic disorder and relieve renal damage induced by diabetes, and that the key mechanisms underlying the positive therapeutic impact of ADMSC treatment in kidneys could be due to the suppression of inflammatory response and oxidative stress. IntroductionDiabetic nephropathy is a major microvascular complication in patients with diabetes and remains the leading cause of chronic kidney disease, accounting for approximately a half of all end-stage renal disease worldwide (1,2). The key pathologic features of diabetic nephropathy include microalbuminurea, mesangial cell (MC) hypertrophy, thickened glomerular and tubular basement membrane, tubulointerstitial fibrosis, and low grade of renal inflammation. It is now well recognized that the pathogenesis of diabetic nephropathy is multifactorial. Over the last decade, diverse pathological mechanisms have been proposed to be involved in the onset and development of diabetic nephropathy, such as genetic and hemodynamic factors, oxidative stress and cytokine signaling (3,4). Nowadays, therapies for diabetic nephropathy have been limited to drugs that improve blood pressure or control blood glucose levels. However, these therapies are not very effective in blocking renal damage and co-treatment with renoprotective drugs often leads to toxicity and reduction in efficacy (5,6). There is thus an imperative need to develop effective therapeutic strategies to preserve normal renal function or to halt the progression of diabetic nephropathy.Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitor cells that can differentiate into a variety of cell types, including osteoblasts, ch...

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“…Neutralizing antibodies against TGF-␤ also have certain beneficial effects on diabetic kidneys (36,50). However, novel pathophysiological pathways identified and targeted are vital to reduce the increasing burden of this disease (39).…”

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confidence: 99%

Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes

Zhang

Yang

Kong

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes. Am J Physiol Endocrinol Metab 300: E287-E295, 2011. First published October 19, 2010 doi:10.1152/ajpendo.00308.2010 is the leading cause of end-stage renal disease. To date, the molecular mechanisms of DN remain largely unclear. The present study aimed to identify and characterize novel proteins involved in the development of DN by a proteomic approach. Proteomic analysis revealed that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2), the key enzyme in ketogenesis, was increased fourfold in the kidneys of type 2 diabetic db/db mice. Consistently, the activity of HMGCS2 in kidneys and 24-h urinary excretion of the ketone body ␤-hydroxybutyrate (␤-HB) were significantly increased in db/db mice. Immunohistochemistry, immunofluorescence, and real-time PCR studies further demonstrated that HMGCS2 was highly expressed in renal glomeruli of db/db mice, with weak expression in the kidneys of control mice. Because filtered ketone bodies are mainly reabsorbed in the proximal tubules, we used RPTC cells, a rat proximal tubule cell line, to examine the effect of the increased level of ketone bodies. Treating cultured RPTC cells with 1 mM ␤-HB significantly induced transforming growth factor-␤1 expression, with a marked increase in collagen I expression. ␤-HB treatment also resulted in a marked increase in vimentin protein expression and a significant reduction in E-cadherin protein levels, suggesting an enhanced epithelial-to-mesenchymal transition in RPTCs. Collectively, these findings demonstrate that diabetic kidneys exhibit excess ketogenic activity resulting from increased HMGCS2 expression. Enhanced ketone body production in the diabetic kidney may represent a novel mechanism involved in the pathogenesis of DN.

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Diabetic nephropathy: Important pathophysiologic mechanisms

Cited by 104 publications

References 42 publications

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Autologous transplantation of adipose-derived mesenchymal stem cells ameliorates streptozotocin-induced diabetic nephropathy in rats by inhibiting oxidative stress, pro-inflammatory cytokines and the p38 MAPK signaling pathway

Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes

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