Xiaoke Decoction Inhibits COX-2-Mediated LDLr Pathway Dysfunction and Protects Renal Function in Diabetic Nephropathy Rats.

Objective: Traditional Chinese medicine exhibits positive therapeutic effects as a primary or adjunctive treatment for diabetic nephropathy (DN). This study aimed to evaluate the impact and mechanism of action of Xiaoke decoction (XKD), a traditional Chinese medicine, on renal function in DN rats.

Methods: A rat model of DN was established, and the rats were divided into five groups (n = 7 per group): normal control group (NC), DN model group (DN), low-dose XKD treatment group (DN + XKD-L, 1.5 g/kg/d), high-dose XKD treatment group (DN + XKD-H, 6 g/kg/d), and cyclooxygenase-2 (COX-2) inhibitor (NS398) treatment group (DN + NS398, 8 mg/kg/d). Medications were administered via gavage for 12 consecutive weeks, while equal volumes of normal saline were given to the NC and DN groups. A glucometer was used to detect changes in blood glucose (BG). Enzyme-linked immunosorbent assay (ELISA) and an automatic biochemical analyzer were employed to measure levels of insulin, serum creatinine (Scr), blood urea nitrogen (BUN), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and 24-h urine protein quantity (UP/24 h) in rats. Renal tissue sections from different treatment groups were prepared, with tissue lesions examined via periodic acid-Schiff (PAS) and hematoxylin-eosin (HE) staining. Tissue inflammation and lipid deposition were evaluated using ELISA and Oil Red O staining. Immunohistochemistry and Western blotting were used to detect changes in the expression levels of COX-2 and low-density lipoprotein receptor (LDLr) in tissues, and to clarify the regulatory mechanism of XKD on renal function in DN rats.

Results: XKD, particularly at the high dose (XKD-H, 6 g/kg/d), significantly reduced BG, insulin levels, renal weight ratio, Scr, BUN, and UP/24 h in DN rats. DN rats showed significant renal lesions, and XKD gavage (especially XKD-H) markedly improved these pathological changes. In DN rats, XKD significantly decreased the protein expression levels of COX-2 and LDLr, downregulated the levels of inflammatory factors and lipid factors, reduced lipid deposition in renal tissues, and ameliorated structural abnormalities in glomeruli, basement membranes, and renal tubules.

Conclusions: XKD alleviates renal tissue damage by regulating the COX-2-mediated LDLr pathway, thereby reducing the release of inflammatory factors and lipid accumulation in DN rats and protecting renal function.