Dapagliflozin attenuates renal tubular senescence in DKD rats by suppressing the CTRP1-SGLT2 glucotoxic axis
Background
Renal tubular senescence is a critical pathological feature and driver of progression in Diabetic Kidney Disease (DKD). While glucotoxic stress is a known contributor to tubular aging, the upstream regulatory mechanisms remain poorly understood. Current standard-of-care, including SGLT2 inhibitors, effectively slows DKD progression, but the full scope of their renoprotective mechanisms, particularly concerning cellular senescence, is still being elucidated. This study investigates the role of C1q/TNF-related protein 1 (CTRP1) as a potential upstream regulator linking glucotoxic stress to tubular senescence and its interaction with SGLT2-mediated glucose uptake.
Study Design
Researchers conducted a retrospective observational case-control analysis of human renal biopsy specimens from DKD patients and controls, using immunohistochemistry and Western blotting to assess protein expression. This was complemented by mechanistic experiments in NRK-52E renal tubular cells to study CTRP1's effect on SGLT2 expression and glucose uptake. An in vivo model of DKD was established in HFD/STZ/UNx rats, where dapagliflozin (0.1 mg/kg/day) was administered daily to evaluate its impact on metabolic abnormalities, renal dysfunction, and tubular senescence markers.
Results
CTRP1 expression progressively increased with DKD severity in human renal cortical tissues and showed a positive correlation with senescence markers p21 (R=0.498) and p16 (R=0.494). Bioinformatic analysis of CTRP1-deficient mice consistently revealed SGLT2 downregulation. In NRK-52E cells, CTRP1 overexpression significantly increased SGLT2 expression and glucose uptake, particularly under hyperglycemic conditions, confirming a direct link. In the HFD/STZ/UNx-induced DKD rat model, dapagliflozin (0.1 mg/kg/day) improved metabolic abnormalities and renal dysfunction, and markedly attenuated tubular senescence. > Dapagliflozin suppressed the CTRP1-SGLT2 axis activation, reduced glucose uptake in renal tubular cells, and significantly decreased the proportion of CTRP1+SGLT2+ double-positive tubular cells, providing strong evidence for this novel signaling pathway.
Key Findings
- CTRP1 expression increased with DKD severity and correlated with senescence markers p21 (R=0.498) and p16 (R=0.494).
- CTRP1 overexpression in renal cells increased SGLT2 expression and glucose uptake, especially under hyperglycemia.
- Dapagliflozin (0.1 mg/kg/day) improved metabolic and renal function in DKD rats.
- Dapagliflozin attenuated tubular senescence and suppressed the CTRP1-SGLT2 axis in DKD rats.
- Dapagliflozin reduced the proportion of CTRP1+SGLT2+ double-positive tubular cells.
Why It Matters
This research provides a novel mechanistic understanding of how SGLT2 inhibitors exert renoprotective effects in DKD, beyond their established glucose-lowering actions. Identifying the CTRP1-SGLT2 axis as a key driver of glucotoxic tubular senescence suggests new therapeutic targets for DKD. For clinicians and biohackers, this reinforces the rationale for SGLT2 inhibitor use in DKD and highlights a specific pathway through which these compounds mitigate cellular aging in the kidney. While the specific dapagliflozin (0.1 mg/kg/day) dose was effective in rats, direct human translation requires further clinical trials, but it deepens our understanding of existing protocols.
dapagliflozin
diabetic kidney disease
dkd
sglt2 inhibitor
renal tubular senescence
ctrp1