大黄甘草汤调控SIRT3/HIF-1α/hepcidin轴抑制肾间质纤维化的作用机制研究OA

Objective To investigate the potential effects and mechanisms of Dahuang Gancao Decoction(大黄甘草汤,DHGCD)on adenine-diet-induced renal interstitial fibrosis(RIF)in mice.Methods A mouse model of RIF was induced by an adenine diet and treated with DHGCD.Renal function was assessed by measuring blood urea nitrogen(BUN)and serum creatinine(Scr)levels.Masson's trichrome staining was used to evaluate renal collagen deposition.The primary sites of iron homeostasis imbalance in the kid-neys were determined by assessing the co-localization of hepcidin and related proteins.Protein levels of SIRT3,HIF-1α,and hepcidin were detected by Western blot(WB).Subsequently,renal function,fibrosis,and iron homeostasis were evaluated in SIRT3-knockout mice to validate the hypothesis.Results In the adenine-diet-induced renal injury mouse model,the primary binding site of hepcidin in the kidneys was localized for the first time to the renal tubular collecting duct.DHGCD intervention significantly attenuated the progres-sion of renal dysfunction and markedly inhibited collagen deposition in renal tissues,indicating anti-renal fibrotic effects.Further mechanistic studies revealed that DHGCD activated SIRT3 expression,reduced the acetylation level of HIF-1α,and suppressed the activation of the hepcidin signaling pathway in the kidneys.However,in SIRT3 knockout mice,DHGCD failed to significantly amelio-rate renal fibrosis or iron metabolism disorders,suggesting that its renal protective effects are dependent on SIRT3 activation.Conclu-sion SIRT3 is a key target regulated by DHGCD.The ability of DHGCD to modulate the SIRT3/HIF-1α signaling pathway may repre-sent a feasible therapeutic approach for RIF.