Proximal Tubule mTORC1 Is a Central Player in the Pathophysiology of Diabetic Nephropathy and Its Correction by SGLT2 Inhibitors

Abstract

Summary Diabetic kidney disease (DKD) increases the risk for mortality and is the leading cause of end-stage renal disease. Treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) attenuates the progression of DKD, especially in patients with advanced kidney disease. Herein, we show that in diabetes, mTORC1 activity is increased in renal proximal tubule cells (RPTCs) along with enhanced tubule-interstitial fibrosis; this is prevented by SGLT2i. Constitutive activation of mTORC1 in RPTCs induces renal fibrosis and failure and abolishes the renal-protective effects of SGLT2i in diabetes. On the contrary, partial inhibition of mTORC1 in RPTCs prevents fibrosis and the decline in renal function. Stimulation of mTORC1 in RPTCs turns on a pro-fibrotic program in the renal cortex, whereas its inhibition in diabetes reverses the alterations in gene expression. We suggest that RPTC mTORC1 is a critical node that mediates kidney dysfunction in diabetes and the protective effects of SGLT2i by regulating fibrogenesis.

Pathogenesis of diabesity‐induced kidney disease: role of kidney nutrient sensing

“…In disagreement with previous reports, we found that KPTC proliferation was reduced rather than increased, and there was no evidence for epithelial-mesenchymal transition, suggesting that tubular cell dedifferentiation does not play a major role in kidney dysfunction in this model [38]. [38]. Importantly, moderate reduction of mTORC1 activity by conditional, heterozygous deletion of Raptor in KPTCs completely prevented fibrosis and preserved kidney function [38].…”

“…Consistent with this paradigm, treatment of KPTCs with SGLT2i decreased glycolytic flux [38] . In disagreement with previous reports, we found that KPTC proliferation was reduced rather than increased, and there was no evidence for epithelial-mesenchymal transition, suggesting that tubular cell dedifferentiation does not play a major role in kidney dysfunction in this model [38]. [38].…”

“…Availability of these AAs is conveyed to mTORC1 via the heterodimeric Rag GTPases, which recruit mTORC1 to the lysosomal surface for activation by the . We found that heterozygous knockout of Raptor in RPTCs of diabetic animals exacerbated glucosuria, proteinuria, sodium, calcium, phosphate and uric acid excretion compared to control diabetic mice [38]. Furthermore, mTORC1 activation by Tsc1 deletion in KPTCs induced polyuria, glucosuria, proteinuria and hypercalciuria.…”

“…In addition, the kidneys account for one-third of whole body leucine production [83], and contribute a substantial fraction of the circulating pool of BCAAs by regulating their proteolysis, uptake, and oxidation [84]. [38]. Collectively, these findings may suggest that AA transport and metabolism are altered in diabetes and play a role in the pathophysiology of DKD.…”

Roles of mTOR in Diabetic Kidney Disease

“…Moreover, the activation of the mTOR pathway is involved in the increased expression of profibrotic cytokines, such as TGF-β1 and connective tissue growth factor, and subsequent interstitial fibrosis of DKD [ 34 , 35 ]. Furthermore, proximal tubular cell-specific Raptor heterozygous-deficient mice exhibit reduced tubular fibrosis and reduced renal function under diabetic conditions [ 36 ]. These results suggest that the abnormal activation of mTORC1 is involved in the pathogenesis of tubular damage in DKD.…”