Integrative metabolomics and lipidomics reveal Jian-Pi-Yi-Shen formula improves adenine-induced CKD rats by regulating intrarenal glycolipid metabolism.

Chronic kidney disease (CKD) is a global health problem with limited therapeutic options. Derangements in glucose and lipid metabolism represent a key feature of CKD that drives tubular injury and fibrosis. The Jian-Pi-Yi-Shen formula (JPYSF), a traditional Chinese medicine prescription, has been used for treating CKD for decades. To clarify metabolic mechanisms underlying the clinical efficacy of the JPYSF, we used an adenine-induced CKD model in male Sprague-Dawley rats, assigning animals to control, CKD, or CKD + JPYSF groups. After 6 weeks, renal function and serum lipids were quantified biochemically. Renal pathology and fibrosis were assessed histologically. Targeted renal metabolomics profiled metabolites associated with glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and gluconeogenesis. Untargeted renal lipidomics characterized lipid profiles of kidney tissues. The results showed that JPYSF improved body weight and kidney index, lowered serum creatinine and urea, attenuated tubular injury and collagen deposition, and reduced α-smooth muscle actin and vimentin, without affecting alanine aminotransferase and aspartate aminotransferase. CKD kidneys displayed heightened glycolysis and PPP intermediates with reduced TCA intermediates and gluconeogenic precursors; JPYSF partially normalized these metabolites and reversed concordant transcriptional changes. Systemically, JPYSF reduced triglycerides and increased high-density lipoprotein cholesterol, with downward trends in total cholesterol and low-density lipoprotein cholesterol. Lipidomics showed extensive CKD-associated remodeling (749 differential lipids; glycerophospholipid and sphingolipid pathways). JPYSF reprogrammed the renal lipidome (64 differential lipids), predominantly restoring glycerophospholipids and dampening sphingolipids, directionally reversing subsets of CKD-perturbed species. In conclusion, JPYSF ameliorates adenine-induced CKD and fibrosis. These beneficial effects are accompanied by the partial restoration of renal glycolipid metabolic homeostasis, suggesting that metabolic regulation may contribute to the therapeutic mechanism of JPYSF.