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

Abstract

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...

Mesenchymal Stem Cell-Based Treatment for Microvascular and Secondary Complications of Diabetes Mellitus

“…The injection of hUMB cord MSCs after induction of hyperglycemia effectively prevented proteinuria and increased fractional mesangial area albeit with a low level of kidney engraftment (112). Autologous transplantation of adipose-derived MSCs minimized pathological alterations, reduced oxidative damage and suppressed the renal expression of pro-inflammatory cytokines in a rodent STZ model of diabetic nephropathy (113). Adipose MSC implantation significantly alleviated all indices of metabolic dysfunction when compared to controls including a reduction in blood glucose.…”

“…Adipose MSC implantation significantly alleviated all indices of metabolic dysfunction when compared to controls including a reduction in blood glucose. Expression of MAPK signaling pathway molecules (p-p38, p-ERK and p-JNK) was also reduced in MSC-treated rodent renal tissues leading the authors to suggest that the positive therapeutic effect of adipose-derived MSCs on diabetic kidneys could be due to suppression of inflammatory response and oxidative stress (113). …”

Challenges and opportunities for stem cell therapy in patients with chronic kidney disease

“…However, direct evidence from glomerulosclerosis and interstitial fibrosis analyses was incomplete. Additionally, Li et al 24 found that human MSCs prevented hyperglycemia-induced podocyte apoptosis and injury, and other investigations have shown that in animal models of diabetic nephropathy, MSCs reduced glomerulosclerosis and oxidative stress 18, 20, 25, 26 . We also previously demonstrated the beneficial effect of EPC and MSC transplantation in a porcine model of renovascular hypertension, wherein intrarenal delivery of cells attenuated renovascular hypertension-induced myocardial injury and decreased renal injury 19, 27, 28 …”

Stem Cell-Based Cell Therapy for Glomerulonephritis

“…Compared with BM-MSCs, adipose-derived MSCs (AD-MSCs) are equally capable of differentiating into cells and tissues of mesodermal origin. In addition, they offer some advantages as an attractive, readily available adult stem cell because of the ease of harvest and their abundance [36]. …”

“…In another study, Chen et al reported that infusion of BMDCs obtained from db / m donors to db / db recipient mice benefited microvascular function, insulin sensitivity, and nephropathy [35]. Fang et al have reported that autologous transplantation of AD-MSCs could ameliorate STZ-induced diabetic nephropathy in rats by inhibiting oxidative stress, proinflammatory cytokines, and the p38 MAPK signaling pathway [36]. In addition, Masoad et al investigated that mononuclear cells treatment was superior to pioglitazone in controlling hyperglycemia, improving the renal structure and function changes, and reducing renal laminin expression associated with STZ-induced diabetic nephropathy in rats [37].…”