SGLT2 inhibitor ameliorates podocyte hypertrophic stress and progression by suppressing the mTOR/p70S6K/cyclin D1 signaling pathway in a model of obesity-related nephropathy

ABSTRACT: Obesity-related nephropathy (ORN) has been a risk factor for chronic kidney disease, end-stage of kidney disease and increased mortality. However, the underlying mechanism and treatment remain unclear. In this study, using Zucker fatty (ZF) rats with non-diabetic obesity model, we revealed that podocyte hypertrophic stress through the activation of the mammalian target of rapamycin (mTOR)/ 70 kDa ribosomal protein S6 kinase (p70S6K)/cyclin D1 signaling pathway leads to the development of ORN, which is suppressed by sodium-glucose co-transporter 2 inhibitor (SGLT2i). Compared with Zucker lean (ZL) rats as control, ZF rats showed marked increases in body weight, urinary protein, urinary sediment podocin (U-sed pod) mRNA excretion, glomerular and podocyte hypertrophy with increasing weeks of age, suggesting that podocyte hypertrophic stress is related to the development of nephropathy. In addition, ZF rats treated with SGLT2i showed decreased body weight, urinary protein, U-sed pod mRNA excretion, glomerular and podocyte hypertrophy, leading to reduced progression of nephropathy. RNA sequencing was performed for the renal cortex and a significant increase in expression of cyclin D1, which is involved in the cell cycle and has a crucial role for cell hypertrophy and proliferation, was observed in ZF rats. Furthermore, increased insulin-like growth factor-1(IGF-1) expression in the renal cortex and increased phosphor S6 expression in podocytes by immunofluorescence staining were also observed, suggesting that the activation of the mTOR/p70S6K/cyclin D1 signaling pathway by obesity-induced IGF-1 elevation may be related to the development of nephropathy. And these changes were suppressed by SGLT2i treatment. Restriction of calories equivalent to those lost by SGLT2i administration did not show as much podocyte protective effect as observed by SGLT2i administration. These findings suggest that SGLT2i may have a podocyte protective effect beyond calorie restriction. Therefore, SGLT2i may represent a new strategy for the treatment of ORN by inhibiting the mTOR/p70S6K/cyclin D1 signaling pathway.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE285091 | GEO | 2026/06/24

REPOSITORIES: GEO