SGLT-2 inhibitors attenuate pattern recognition molecules collectin kidney 1 and mannose-binding lectin in kidney and liver in mice with diabetes

Background: SGLT-2 inhibitors improve outcomes in diabetic nephropathy (DN) and cardiovascular disease. To elucidate the underlying protective mechanisms, we explored the hypothesis that the lectin complement pathway, specifically through collectin kidney 1(CL-K1), plays a critical role in early DN. We assessed:(1) CL-K1 abundance in the kidneys of diabetic mice; (2) the impact of SGLT-2 inhibition on CL-K1 and complement activation; and (3) the effect of CL-K1 deficiency on albuminuria and epithelial injury. Methods: Streptozotocin (STZ) was used to induce diabetes in male wildtype (WT) and CL-K1 knockout (KO) mice in three sub-studies. The studies evaluated time-dependent effects (14 and 35 days), the effect of dapagliflozin, and the effect of CL-K1 gene deletion. Urine, plasma, and organ samples were analyzed for CL-K1 mRNA and protein levels by qPCR, Western blotting, and in situ hybridization. Results: STZ-treated mice displayed elevated plasma glucose, increased kidney weight, urinary excretion of albumin and kidney injury molecule-1. Kidney and plasma CL-K1 protein levels increased significantly and progressively in STZ-treated mice, while hepatic CL-K1 remained unchanged. Plasma mannose-binding lectin-C (MBL-C) and MASP-1, as well as kidney CL-K1 and MBL-C mRNAs increased following STZ. Dapagliflozin reduced fasting blood glucose(p<0.01), kidney(p<0.05) and hepatic(p<0.05) CL-K1 protein abundance, and plasma MBL-C levels(p<0.01), without affecting mRNA levels. CL-K1 KO STZ mice exhibited a transient significant reduction in the albumin-creatinine ratio after two weeks compared to WT STZ(p<0.0001). Conclusion: Dapagliflozin reduced diabetes-related lectin pathway molecule levels in liver and kidney, potentially protecting the kidney through inhibition of this pathway.