Mesenchymal stem cells ameliorate diabetic glomerular fibrosis in vivo and in vitro by inhibiting TGF-β signalling via secretion of bone morphogenetic protein 7

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide,1 with a significant increase in morbidity and mortality in patients with diabetes.2 Considering that currently available treatments involving strict glycaemic and/or blood pressure control can delay but not eliminate the occurrence and development of DN, it is necessary to identify new strategies that could specifically target on DN.

Structural abnormalities of DN include hypertrophy of the kidney, an increase in the thickness of glomerular basement membrane, accumulation of extracellular matrix (ECM) components in the glomerulus (nodular and diffuse glomerulosclerosis (GS)), tubular atrophy and interstitial fibrosis, typically characterized by ECM accumulation. The transforming growth factor beta (TGF-β) is a multifunctional cytokine that regulates the proliferation and metabolism of ECM proteins3 and considered as one of the main cytokines that aggravates DN.4,5 TGF-β binds to its receptor, TGF-β receptor IIβ, which activates the TGF-β receptor I (TβRI) kinase. Activated TβRI then phosphorylates receptor-regulated Smads (R-Smads), Smad2 and Smad3. Phosphorylated Smad2 and Smad3 form an oligomeric complex with Smad4. The complex translocates into the nucleus and regulates the target gene transcription.6 Besides, TGF-β is also considered to induce epithelial-to-mesenchymal transition (EMT) of the injured tubule epithelial cells.7 Up-regulation of TGF-β and its downstream Smad cascade is prevalent in many types of kidney diseases. More important, several experimental studies have shown that different therapeutic strategies which can inhibit TGF-β signalling pathway can prevent or even reverse the early features of DN.810 Thus, these results provide clear evidence that TGF-β activity contributes importantly to the development of diabetic GS.

Published on 01-15-2018
Authors: Shasha Lv, Gang Liu, Aili Sun, Jianping Wang, Jing Cheng, Weiwei Wang, Xiangchun Liu, Huibin Nie, Guangju Guan