Exploring the molecular mechanisms for renoprotective effects of Huangkui capsule on diabetic nephropathy mice by comprehensive serum metabolomics analysis.

Ethnopharmacological Relevance: Huangkui capsule (HKC), a patent traditional Chinese medicine, has shown significant efficacy in managing chronic kidney disease (CKD), particularly diabetic nephropathy (DN). Previous studies have shown that HKC can alleviate kidney damage in DN. However, the exact mechanisms through which it exerts its effects remain unclear.

Aim Of The Study: This study aimed to elucidate the potential molecular mechanisms of HKC in treating kidney injury in type 1 diabetic nephropathy (T1DN) models through serum metabolomics, Chinmedomics, and molecular docking techniques.

Materials And Methods: T1DN mouse models were induced by intraperitoneal injection of streptozotocin (STZ), resulting in the ACR value ten times that of the control group. The efficacy of HKC on T1DN was comprehensively evaluated in general conditions, renal coefficient, histopathology, and related biochemical indicators. UPLC-Q-TOF-MS/MS based serum metabolomics was employed to identify biomarkers of T1DN and evaluate the effects of HKC. Relevant pathways were analyzed, and followed by Protein-Protein Interaction network analysis to screen for key enzymes. By integrating the Chinmedomics strategy and molecular docking the relationship between these targets and active components was elucitaed.

Results: HKC resulted in a significant reduction in renal inflammation and fibrosis, as evidenced by the decreased levels of urinary ACR, blood TG, T-CHO, BUN, and renal TNF-α and VEGF-A, along with a reduction in the positive area of COL-1. Palmitic acid, stearic acid, arachidonic acid, pantothenic acid, and sphingosine-1-phosphate serve as key serum metabolite biomarkers for T1DN, involved in the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, pantothenate and CoA biosynthesis, and sphingolipid metabolism. FASN, Cyp2e1, and Cyp4a32 are the key enzymes in the treatment of T1DN with HKC. Additionally, 8 key active components were identified in the serum of HKC-H, including quercetin, myricetin, isoquercitrin, hyperoside, hibifolin, gentisic acid 5-O-β-glucoside, floramanoside F, and quercetin-4'-O-glucoside, which are believed to interact with key enzymes.

Conclusions: The active components of HKC influence Fasn, Cyp2e1, and Cy4a32, improving renal injury in T1DN. These findings provide new molecular insights for the future clinical application and research of HKC in treating T1DN.