Empagliflozin alleviates lipid deposition and inflammation in diabetic kidney disease by downregulating C1QC

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 significantly reduced renal C1QC expression, lipid deposition, and inflammation compared with untreated db/db mice (P < 0.05). This study established C1QC as a critical molecular node linking tubular metabolic stress with renal inflammation in DKD. The SGLT2 Inhibitor empagliflozin confers renoprotection through partial C1QC downregulation, suggesting combinatorial therapies targeting C1QC may enhance therapeutic efficacy.

C1QC; Diabetic kidney disease; Empagliflozin; Inflammation; Lipid accumulation.