Empagliflozin alleviates lipid deposition and inflammation in diabetic kidney disease by downregulating C1QC.
Abstract
Our previous study has identified C1QC as a potential mediator through which obesity accelerates the progression of diabetic kidney disease (DKD). Emerging evidence suggests that empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mitigates renal injury by downregulating C1QC expression. This study systematically investigated the mechanistic role of C1QC in DKD pathogenesis and validated empagliflozin's therapeutic effects through C1QC modulation, thereby establishing a novel target for DKD management. Human proximal tubular (HK-2) cells were challenged with high glucose (HG) (30 mM) and palmitate (PA) (300 µM) to establish metabolic injury models. Subsequent interventions included: (1) siRNA-mediated C1QC silencing; (2) C1QC overexpression via plasmid transfection; (3) empagliflozin (500 nM) co-treatment. For in vivo validation, 8-week-old male db/db mice (n = 12) and db/m controls (n = 12) were randomized into four cohorts (n = 6 per group): (1) db/m + vehicle; (2) db/db + vehicle; (3) db/m + empagliflozin (10 mg/kg/d); (4) db/db + empagliflozin (10 mg/kg/d). HG/PA treatment induced C1QC overexpression in HK-2 cells (P < 0.05). C1QC knockdown or empagliflozin treatment attenuated lipid accumulation and inflammation, whereas C1QC overexpression exacerbated these pathological changes (P < 0.05). Rescue experiments revealed that C1QC overexpression partially reversed the protective effects of empagliflozin (P < 0.05). In db/db mice, empagliflozin treatment…
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