Liraglutide Mitigates Renal Injury in Diabetic Kidney Disease by Suppressing Podocyte Cholesterol Accumulation Through mTOR / VMP1 ‐Regulated Autophagy

ABSTRACT Diabetic kidney disease (DKD) is seriously threatening the health of hundreds of millions of diabetes patients worldwide. Research has revealed that liraglutide attenuates renal damage in DKD rats by upregulating autophagic activity. Moreover, autophagy activity can affect cholesterol transport. Nevertheless, it is unclear whether liraglutide improves cholesterol accumulation in DKD rats by regulating autophagy. The DKD model was constructed by performing unilateral nephrectomy on high‐fat diet (HFD) rats, followed by intraperitoneal injection of streptozotocin (STZ). The fasting blood glucose (FBG), albumin (ALB), creatinine (Cr), cholesterol, and triglyceride (TG) were measured by kits. The pathological changes in rat kidneys were observed through hematoxylin and eosin (H&E) and periodic acid‐Schiff (PAS) staining. An in vitro model of DKD was established by exposing podocytes to high glucose. The levels of Nephrin and Podocin in the kidneys or podocytes were measured by immunofluorescence. Filipin III staining was used to measure the cholesterol accumulation. The protein levels of microtubule‐associated protein 1 light chain 3 (LC3), P62, Beclin‐1, mammalian target of rapamycin (mTOR), vacuole membrane protein 1 (VMP1), and ATP‐binding cassette transporter A1 (ABCA1) were assessed by western blot. Liraglutide demonstrated significant efficacy in mitigating hyperglycemia and modulating dyslipidemia in DKD rats, evidenced by marked reductions in FBG, low‐density lipoprotein cholesterol (LDL‐C), TG, and total cholesterol (Tch), while concurrently elevating high‐density lipoprotein cholesterol (HDL‐C) levels. Furthermore, liraglutide promotes autophagy. Additionally, liraglutide upregulates the expression of ABCA1, which alleviates cholesterol accumulation in the kidneys of DKD rats. Both in vivo and in vitro studies have confirmed that liraglutide reduces podocyte cholesterol accumulation in DKD by enhancing autophagy through the mTOR/VMP1 pathway. Liraglutide reduces podocyte cholesterol accumulation through mTOR/VMP1‐mediated autophagy, thereby alleviating renal injury in DKD.