Mesenchymal stem cells prevent the progression of diabetic nephropathy by improving mitochondrial function in tubular epithelial cells

Abstract

The administration of mesenchymal stem cells (MSCs) was shown to attenuate overt as well as early diabetic nephropathy in rodents, but the underlying mechanism of this beneficial effect is largely unknown. Inflammation and mitochondrial dysfunction are major pathogenic factors in diabetic nephropathy. In this study, we found that the repeated administration of MSCs prevents albuminuria and injury to tubular epithelial cells (TECs), an important element in the progression of diabetic nephropathy, by improving mitochondrial function. The expression of M1 macrophage markers was significantly increased in diabetic kidneys compared with that in control kidneys. Interestingly, the expression of arginase-1 (Arg1), an important M2 macrophage marker, was reduced in diabetic kidneys and increased by MSC treatment. In cultured TECs, conditioned media from lipopolysaccharide-activated macrophages reduced peroxisomal proliferator-activated receptor gamma coactivator 1α (Pgc1a) expression and impaired mitochondrial function. The coculture of macrophages with MSCs increased and decreased the expression of Arg1 and M1 markers, respectively. Treatment with conditioned media from cocultured macrophages prevented activated macrophage-induced mitochondrial dysfunction in TECs. In the absence of MSC coculture, Arg1 overexpression in macrophages reversed Pgc1a suppression in TECs. These observations suggest that MSCs prevent the progression of diabetic nephropathy by reversing mitochondrial dysfunction in TECs via the induction of Arg1 in macrophages.

Mouse Umbilical Cord Mesenchymal Stem Cell Paracrine Alleviates Renal Fibrosis in Diabetic Nephropathy by Reducing Myofibroblast Transdifferentiation and Cell Proliferation and Upregulating MMPS in Mesangial Cells

“…In diabetic animals, pathological examination shows significant glomerular mesangial expansion, matrix expansion accumulation, and basement membrane thickening [39][40][41]. Previous studies have shown that mesangial cell proliferation is responsible for observed ECM accumulation and mesangial expansion [42,43].…”

The future of diabetic kidney disease management: what to expect from the experimental studies?

“…Moreover, Takemura et al showed that transplantation of ad-MSCs under the renal capsule of Spontaneously Diabetic Torii fatty rats attenuates glomerular and tubular injury to a greater extend compared to ad-MSCs administrated per intravenous route [59]. Finally, Lee SE et al have shown that treatment with ad-MSCs prevented albuminuria and tubular epithelial cell injury via induction of the Arginase-1, a marker of M2 macrophages, and subsequent improvement of mitochondrial function [60] Although these pre-clinical studies in DKD suggest that MSC-based therapy may represent a novel promising tool for DKD treatment, the experimental design of these studies is heterogeneous in terms of cell types, doses, administration route, diabetes duration, making it difficult to translate these findings into clinical practice. In addition, the use of MSCs has several limitations.…”

Mesenchymal Stem Cells Attenuate Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress Responses in Rats

“…MSCs harbor differentiation potential, immunosuppressive properties, and anti-inflammatory effects and are considered an ideal candidate cell type for the treatment of DM [32]. MSCs are found to ameliorate various diabetic complications, such as diabetic cardiomyopathy, retinopathy, nephropathy, peripheral neuropathy, and foot ulcer [33][34][35][36][37]. In our previous works, we also found that MSCs ameliorate hyperglycemia-induced endothelial injury [38,39] and diabetic kidney injury [40].…”