Sodium-glucose cotransporter 2 inhibitor ameliorates podocyte hypertrophic stress by suppressing the mTOR/p70S6K/cyclin D1 signaling pathway in obesity-related nephropathy.

Obesity-related nephropathy (ORN) is a risk factor for chronic kidney disease, end-stage kidney disease, and increased mortality. However, the underlying mechanism and treatment of ORN remain unknown. Compared to Zucker lean rats (control), Zucker fatty (ZF) rats, a nondiabetic obesity model, showed marked increases in body weight, urinary protein excretion, urinary sediment podocin (U-sed pod) mRNA levels, and glomerular/podocyte hypertrophy with age, implying that podocyte hypertrophic stress is linked to ORN development. Conversely, sodium–glucose cotransporter 2 inhibitor (SGLT2i) administration decreased body weight, urinary protein, U-sed pod mRNA excretion, and glomerular/podocyte hypertrophy. RNA sequencing of the renal cortex in ZF rats showed increased cyclin D1 expression and elevated protein levels of cyclin D1, IGF-1, and phospho S6 levels, indicating that IGF-1-mediated activation of the mTOR/p70S6K/cyclin D1 signaling pathway is involved in ORN. These changes were restored via SGLT2i treatment. Furthermore, the protective effects of SGLT2i on podocytes partially exceeded those of calorie restriction equivalent to the calorie loss from urinary glucose excretion. These results indicate that SGLT2i suppresses the IGF-1-mediated mTOR/p70S6K/cyclin D1 signaling pathway and reduces glomerular/podocyte hypertrophic stress. This represents a novel mechanism for the podocyte-protective effect of SGLT2i and underscores their potential as a therapeutic strategy for ORN.