Decreasing S1PR3 Alleviated Renal Tubular Lipid Deposition in Diabetic Nephropathy via AMPK/PPAR-γ/GPAT3 Pathway.

To investigate the role of S1PR3 in ectopic lipid deposition in diabetic nephropathy (DN) and its underlying mechanisms. The DN rat model was constructed and treated with adeno-associated virus (AAV9) cloned with S1PR3 overexpression or knockdown on the 7th and 49th day after STZ injection. Rat body weight, fasting plasma glucose (FPG), 24-hour urine output and urine protein, renal function, and blood lipids were all tested at different time points after AAV9 injection. 12 weeks post-AAV9 injection, pathological changes and ectopic lipid deposition in renal tissue were detected. In addition, to validate the role of AMPK/PPAR-γ/GPAT3 pathway, we applied AMPK activator MK-8722 and PPAR-γ inhibitor GW9662. S1PR3 was highly expressed in DN rats. Low S1PR3 reduced FPG and body weight, improved blood lipid profiles, and enhance renal function. Additionally, they promoted lipid hydrolysis and inhibited lipid synthesis, thereby reducing ectopic lipid deposition and protecting against diabetic nephropathy in DN rats. High S1PR3 expression had the opposite effect. Low S1PR3 activated AMPK, thereby downregulating PPARγ and GPAT3. The application of MK-8722 and GW9662 altered the beneficial effects produced by S1PR3 knockdown. These changes in lipid metabolism were attributed to low S1PR3 levels upregulating the AMPK/PPAR-γ/GPAT3 pathway. Collectively, low S1PR3 levels inhibited lipid synthesis and promote hydrolysis, reducing blood lipids and alleviating renal ectopic lipid deposition in DN rats. These changes caused by knocking down S1PR3 may be related to the AMPK/PPAR-γ/GPAT3 pathway.