Abstract
Mesenchymal stem cells (MSCs) are shown to alleviate renal injury of diabetic nephropathy (DN) in rats. However, the underlying mechanism of this beneficial effect is not fully understood. The aims of this study are to evaluate effects of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on renal cell apoptosis in streptozotocin- (STZ-) induced diabetic rats and explore the underlying mechanisms. Characteristics of UC-MSCs were identified by flow cytometry and differentiation capability. Six weeks after DN induction by STZ injection in Sprague-Dawley rats, the DN rats received UC-MSCs once a week for consecutive two weeks. DN-related physical and biochemical parameters were measured at 2 weeks after UC-MSC infusion. Renal histological changes were also assessed. Moreover, the apoptosis of renal cells and expression of apoptosis-related proteins were evaluated. Compared with DN rats, rats treated with UC-MSCs showed suppressed increase in 24-hour urinary total protein, urinary albumin to creatinine ratio, serum creatinine, and blood urea nitrogen. UC-MSC treatment ameliorated pathological abnormalities in the kidney of DN rats as evidenced by H&E, PAS, and Masson Trichrome staining. Furthermore, UC-MSC treatment reduced apoptosis of renal cells in DN rats. UC-MSCs promoted expression of antiapoptosis protein Bcl-xl and suppressed expression of high mobility group protein B1 (HMGB1) in the kidney of DN rats. Most importantly, UC-MSCs suppressed upregulation of thioredoxin-interacting protein (TXNIP), downregulation of thioredoxin 1 (TRX1), and activation of apoptosis signal-regulating kinase 1 (ASK1) and P38 MAPK in the kidney of DN rats. Our results suggest that UC-MSCs could alleviate nephrocyte injury and albuminuria of DN rats through their antiapoptotic property. The protective effects of UC-MSCs may be mediated by inhibiting TXNIP upregulation in part.
Highlights
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus (DM) and the leading cause of end-stage renal disease worldwide [1, 2]
diabetic nephropathy (DN) is clinically characterized by albuminuria and reduced renal function evidenced by a decreased glomerular filtration rate (GFR) and increased serum creatinine and blood urea nitrogen concentration [4]
The in vitro expanded UC-Mesenchymal stem cells (MSCs) at passage 5 (P5) used in this study were characterized by plastic adherence and their typical fibroblastlike morphology (Figure 1(a)), multilineage differentiation potential (Figures 1(b) and 1(c)), and immunophenotype (Figure 1(d))
Summary
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus (DM) and the leading cause of end-stage renal disease worldwide [1, 2]. About one-third of type 1 DM (T1DM) and a quarter of type 2 DM (T2DM) patients eventually develop DN [3]. DN is clinically characterized by albuminuria and reduced renal function evidenced by a decreased glomerular filtration rate (GFR) and increased serum creatinine and blood urea nitrogen concentration [4]. DN is featured by glomerular mesangial expansion, increased extracellular matrix deposition, thickened glomerular and tubular basement membranes, renal inflammation, and fibrosis [5]. Drugs that control the blood glucose level, decrease blood pressure, or inhibit actions of the renin-angiotensin system may delay but not eliminate the progression of DN [6]. Development of novel therapeutic strategies that could target the pathogenesis of DN is necessary
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