SGLT2 Inhibition Attenuates Renal Tubular Senescence by Suppressing CTRP1-Mediated Glucotoxic Stress in Diabetic Kidney Disease.

Renal tubular senescence is a defining pathological feature of diabetic kidney disease (DKD) and a key driver of disease progression. While glucotoxic stress is recognized as a major contributor to tubular aging, the upstream regulatory mechanisms remain incompletely understood. Here, we investigated the role of C1q/TNF-related protein 1 (CTRP1) in DKD-associated tubular senescence and its mechanistic link to SGLT2-mediated glucose uptake. We conducted a retrospective observational case-control analysis of human renal biopsy specimens, complemented by mechanistic experiments in NRK-52E cells and a high-fat diet/streptozotocin/uninephrectomy (HFD-STZ-UNx) rat model. Renal cortical tissues from DKD patients and controls were analyzed via immunohistochemistry and Western blotting. CTRP1 expression increased progressively with DKD severity and was positively correlated with the senescence markers p21 (R = 0.498) and p16 (R = 0.494). Bioinformatic analysis of CTRP1-deficient mice revealed consistent SGLT2 downregulation, which was validated experimentally in NRK-52E cells, where CTRP1 overexpression increased SGLT2 expression and glucose uptake, particularly under hyperglycemic conditions. In HFD/STZ/UNx-induced DKD rats, dapagliflozin (0.1 mg/kg/day) improved metabolic abnormalities and renal dysfunction and attenuated tubular senescence. Dapagliflozin suppressed CTRP1-SGLT2 axis activation, reduced glucose uptake in renal tubular cells, and markedly decreased the proportion of CTRP1+SGLT2+ double-positive tubular cells. These findings support the presence of a previously unrecognized CTRP1-SGLT2 signaling axis associated with glucose-mediated tubular senescence in DKD and provide mechanistic insight into SGLT2 inhibitor-mediated renoprotection.