Bupi Yishen formula improves chronic kidney disease by restoring renal energy metabolism and mitochondrial oxidative phosphorylation.

BACKGROUND

Bupi Yishen formula (BYF) is a traditional Chinese herbal mixture with proven efficacy in attenuating kidney function deterioration among patients with advanced chronic kidney disease (CKD), and improving renal fibrosis of CKD animal models. Previous studies have shown that BYF rehabilitates metabolic dysregulation under CKD condition, but its exact mechanism remains unclear.

PURPOSE

This study aimed to elucidate the therapeutic effect and its potential mechanism on regulating renal energy metabolism in CKD.

METHODS

An adenine-induced CKD rat model was treated with two doses of BYF decoction (15 g/kg/day or 30 g/kg/day) and losartan (as the positive control) for 4 weeks. Lipidomic and transcriptomic analyses of kidney samples from CKD rats revealed the BYF-reversed different lipid species and gene expression profiles respectively, thereby identifying potential pharmacological mechanisms. Further in vivo and in vitro experiments, network analyses, and molecular docking was used to confirm the proposed mechanisms affected by BYF.

RESULTS

BYF had a profound impact on alleviating renal impairment and profibrotic phenotypes in CKD rats. Lipid profiling of kidneys from CKD rats showed that the dysmetabolism of glycerophospholipids, sphingolipids, and glycerolipids was primarily influenced by BYF. Transcriptome analysis of CKD rats identified renal energy metabolism (including fatty acid oxidation [FAO], glucose metabolism) and mitochondrial oxidative phosphorylation (OXPHOS) as the key dysregulated pathways, which were reversed by BYF. Further experiments confirmed that BYF partially restored defective FAO, dysregulated glucose metabolism, and impaired mitochondrial OXPHOS in the kidneys of CKD rats and TGFβ1-induced human tubule HK-2 cells. Besides, network analyses combined with molecular docking demonstrated a strong binding effect of BYF's core compounds on key targets related to energy metabolism.

CONCLUSIONS

These results suggest that BYF protects against CKD by restoring renal energy homeostasis and mitochondrial OXPHOS, offering potential as an alternative therapy for renal fibrosis inherent to CKD.