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

Sodium-glucose cotransporter-2 (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: <i>1</i>) CL-K1 abundance in the kidneys of diabetic mice, <i>2</i>) the impact of SGLT-2 inhibition on CL-K1 and complement activation, and <i>3</i>) the effect of CL-K1 deficiency on albuminuria and epithelial injury. Streptozotocin (STZ) was used to induce diabetes in male wild-type (WT) and CL-K1 knockout (KO) mice in three substudies. The studies evaluated time-dependent effects (14 days and 35 days), the effect of dapagliflozin, and the effect of <i>COLEC11</i> gene deletion. Urine, plasma, and organ samples were analyzed for CL-K1 mRNA and protein levels by quantitative polymerase chain reaction (qPCR), Western blotting, and in situ hybridization. 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, whereas hepatic CL-K1 remained unchanged. Plasma mannose-binding lectin-C (MBL-C) and mannose-binding lectin (MBL)-associated serine proteases (MASP-1), as well as kidney CL-K1 and MBL-C mRNAs increased following STZ. Dapagliflozin reduced fasting blood glucose (<i>P</i> < 0.01), kidney (<i>P</i> < 0.05), and hepatic (<i>P</i> < 0.05) CL-K1 protein abundance, and plasma MBL-C levels (<i>P</i> < 0.01), without affecting mRNA levels. CL-K1 KO STZ mice exhibited a transient significant reduction in the albumin-creatinine ratio after 2 wk compared with WT STZ (<i>P</i> < 0.0001). Dapagliflozin reduced diabetes-related lectin pathway molecule levels in liver and kidney, potentially protecting the kidney through inhibition of this pathway.<b>NEW & NOTEWORTHY</b> This study investigated how SGLT-2 inhibitors (SGLT-2is) could improve kidney outcomes in early stages of diabetic nephropathy (DN) by examining changes in and contribution of collectins. We found that levels of collectin [CL-K1 and mannose-binding lectin (MBL)] increase in the kidneys of diabetic mice as injury progresses, and SGLT-2is reduce these levels. Notably, CL-K1 deletion offered temporary protection against filtration barrier injury. These findings suggest that collectins are involved in the early stages of DN, and SGLT-2is might protect the kidneys by influencing collectin activity and reducing inflammation.