Shen-Shuai-II-Recipe inhibits aerobic glycolysis through SIRT1 in 5/6 ablation/infarction renal failure model

Renal fibrosis is the common pathological feature of chronic kidney diseases, which is in parallel with increasing energy demand in proximal tubular epithelial cells during the metabolic shift from fatty acid oxidation to glycolysis. Shen-Shuai-II-Recipe (SSR) is a traditional Chinese medicine formula with known renal benefits in patients with chronic kidney disease (CKD) and has been shown to intervene in renal energy metabolism in a rodent model of CKD. We aimed to explore the mechanism underlying the protective effect of SSR against CKD. A 5/6 ablation/infarction (A/I) renal failure model was established in rats, followed by 8 weeks of gavage feeding with SSR or Losartan, a positive control. For in vitro experiments, normal rat kidney-52E (NRK-52E) cells were cultured under hypoxic condition (1% O₂) or normoxic condition. The expression of fibrotic markers and aerobic glycolysis-related enzymes were determined by Western blotting analysis. The concentration of metabolites was also measured. The concentration of lactic acid was increased, and the concentration of pyruvic acid was decreased in vitro and in vivo models, which were correlated with increased expression of glycolysis-related enzymes Hexokinase2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), SSR treatment reversed the changes of renal glycolysis in cells and animals, which was associated with reduced expression of fibrotic markers such as fibronectin and α-SMA. Mechanistically, SSR treatment enhanced the expression of Sirtuin 1 (SIRT1) and reduced the expression of Hypoxia-Inducible Factor 1-alpha (HIF-1α) in vitro and in vivo models. Downregulation of SIRT1 by small interfering ribonucleic acid (siRNA) reversed the anti-fibrotic effect and anti-glycolysis effect of SSR in renal cells. SSR exerts an anti-fibrotic effect and inhibits renal aerobic glycolysis in CKD via the regulation of SIRT1/HIF-1α.