Tanshinone I improves renal fibrosis by promoting gluconeogenesis through upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α

BackgroundRenal fibrosis, a hallmark of chronic kidney disease, is closely associated with dysregulated gluconeogenesis. Tanshinone I (Tan I), a bioactive compound derived from the traditional Chinese medicine Danshen, exhibits antifibrotic and anti-inflammatory properties. However, its effects on gluconeogenesis and the mechanisms through which it alleviates renal fibrosis remain unclear. This study aimed to investigate whether Tan I promotes gluconeogenesis and mitigates renal fibrosis.MethodsBoth in vivo and in vitro experiments were conducted. A unilateral ureteral obstruction (UUO) mouse model was used. Masson's trichrome, HE, and immunofluorescence staining, along with Western blotting, were employed. Lactate concentrations and a pyruvate tolerance test were conducted to assess glucose metabolism. In vitro, HK2 cells and primary renal tubular cells were treated with transforming growth factor-beta (TGF beta) to induce fibrosis, and the effects of Tan I on glucose and lactate levels were examined.ResultsIn the UUO model, Tan I reduced fibrosis, decreased lactate accumulation, and modulated fibrosis markers while upregulating gluconeogenesis markers. Tanshinone I restored impaired renal gluconeogenesis, as evidenced by increased pyruvate levels. In vitro, Tan I inhibited fibrosis, reduced lactate levels, and increased glucose levels in cell supernatants. It also restored gluconeogenesis protein expression and decreased fibrotic protein levels. Peroxisome proliferator-activated receptor-gamma coactivator (PGC1 alpha) expression was downregulated in UUO and TGF beta-stimulated models, and Tan I reversed this downregulation. Inhibition of PGC1 alpha in TGF beta-stimulated cells counteracted the antifibrotic and gluconeogenesis-promoting effects of Tan I.ConclusionsTanshinone I ameliorated renal fibrosis by enhancing gluconeogenesis through upregulation of PGC1 alpha.