三七总皂苷调控SLC7A11/GSH/GPX4信号通路缓解肾纤维化OA

Objective:To investigate whether Notoginseng Total Saponins(PNS)inhibit ferroptosis and delay renal fibrosis by regulating the solute carrier family 7 member 11(SLC7A11)/glutathione(GSH)/glutathione peroxidase 4(GPX4)pathway.Methods:Forty-eight male SD rats were randomly allocated into sham operation,model control,PNS(0.04,0.08,and 0.16 g/kg),and ferroptosis inhibitor(5 mg/kg)groups,with 8 rats in each group.The rat model of renal fibrosis was established by unilateral ureteral obstruction(UUO).Rats were administrated with corresponding drugs by gavage,and the fibrosis inhibitor was administered by intraperitoneal injection,once a day,for 14 days.The lev-els of serum creatinine(Scr)and blood urea nitrogen(BUN)in the blood collected from abdominal aorta were meas-ured.Renal tissue samples were collected,and the pathological changes and collagen deposition in the renal tissue were observed by HE and Masson staining.The kidney ultrastructure was observed by transmission electron microscopy.The content of malondialdehyde(MDA)was determined by ELISA.Bioassay kits were used to determine the activity of su-peroxide dismutase(SOD),the level of GSH,and the level of Fe2+in renal tissue of rats in each group.The expression of SLC7A11 and GPX4 in renal tissue of each group was detected by immunohistochemistry.The protein levels of SLC7A11 and GPX4 were quantified by Western blot.Results:Compared with the sham operation group,the model con-trol group showed elevated Scr and BUN levels(P<0.05),glomerulosclerosis,renal tubule atrophy,interstitial inflamma-tory cell infiltration,necrosis and exfoliation of some tubule epithelial cells,and obvious renal fibrosis,increased collagen volume fraction,and a large number of collagen fibers dyed blue,small and disarranged damaged mitochondria with irreg-ular shapes,reduced or disappeared cristae,and swelling and vacuole in some mitochondria,declined levels of MDA,SOD,GSH,and Fe2+,and down-regulated protein levels of SLC7A11and GPX4 in the renal tissue(P<0.05).Compared with the model control group,PNS at different doses and ferroptosis inhibitor lowered the levels of Scr and BUN(P<0.05),alleviated the pathological changes in glomeruli and renal tubules,reduced the interstitial inflammatory cell infil-tration,mitigated fibrosis,decreased the collagen volume fraction and blue collagen fibers,improved the structure,mor-phology,and arrangement of mitochondria,elevated the MDA,SOD,GSH,and Fe2+levels in the renal tissue,and up-regu-lated the protein levels of SLC7A11and GPX4(P<0.05).High-dose PNS demonstrated the best performance.Conclu-sion:PNS may inhibit ferroptosis of renal tubular epithelial cells by up-regulating the SLC7A11/GSH/GPX4 signaling pathway,thus delaying renal fibrosis.