mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

Abstract

Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics.Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocytespecific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalization of slit diaphragm proteins and induced an epithelial-mesenchymal transition-like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN.

A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity

“…In addition to renal tubular cells, increased immunohistochemical staining for p62 and p-S6RP in glomerular podocytes was observed. Previous studies have shown that the activation of mTORC1 in glomerular podocytes plays a crucial role in the pathogenesis of diabetic nephropathy [25,26]. However, it remains unclear whether mTORC1 activation in podocytes contributes to the suppression of autophagy in diabetes.…”

“…The mammalian target of rapamycin complex 1 (mTORC1) pathway is activated by a state of overnutrition, resulting in the suppression of autophagy. Previous reports have shown that mTORC1 activity is increased in renal cells, including tubular cells, in the diabetic state [24][25][26]. Because amino acids are recognised as mTORC1 activators [27], an LPD, which involves amino acid restriction, should suppress the mTORC1 pathway.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Pathways contributing to podocyte injury and glomerulosclerosis (100) amongst others include the epidermal growth factor receptor (EGFR) (90), mTOR (101)(102)(103), angiotensin II (104), miR-193a (105), KLF-4 (106), adiponectin (107), RAP1GAP (82), or Rho-A (108). Apart from necrosis, apoptosis or mitotic catastrophe, migration of podocytes onto Bowman's capsule, has been suggested as a novel mechanism of podocytes loss (109,110).…”

Advanced glycation end‐products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

“…It is the most studied regulator of autophagy; it inhibits autophagy initiation by phosphorylation of autophagy‐related proteins 5. mTOR is hyperactivated in patients with DN 6, and reduction of mTOR activity in animals suffering from diabetes mellitus (DM) suppresses DN development 7, 8.…”