Mechanism of ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radix regulates HIF-1α signaling pathway mediated by renal hypoxia to ameliorate renal fibrosis in DKD rats
This study explored the mechanism of the ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radix in ameliorating renal fibrosis in the rat model of diabetic kidney disease(DKD)based on the expression of hypoxia-inducible factor-1α(HIF-1α)/vascular endothelial growth factor(VEGF)and HIF-1α/platelet-derived growth factor(PDGF)/platelet-derived growth factor receptor(PDGFR)signaling pathways in the DKD rats.After 1 week of adaptive feeding,50 male SPF-grade Wistar rats were randomized into a blank group(n=7)and a modeling group.After 24 h of fasting,the rats in the modeling group were subjected to intraperitoneal injection of streptozocin and fed with a high-sugar and high-fat diet to establish a DKD model.After modeling,the rats were randomly assigned into model(n= 7),low-dose ultrafiltration extract(n= 7),medium-dose ultrafiltration extract(n= 7),irbesartan(n=8),and high-dose ultrafiltration extract(n=8)groups.After intervention by corresponding drugs for 12 weeks,the general conditions of the rats were observed.The body weights and blood glucose levels of the rats were measured weekly,and the 24 h urinary protein(24hUP)was measured at the 6th and 12th weeks of drug administration.After the last drug administration,the renal function indicators were determined.Masson staining was employed to observe the pathological changes of the renal tissue.The expression of prolyl hydroxylase domain 2(PHD2)and HIF-1α in the renal tissue was detected by immunohistochemistry(IHC).Real-time qPCR was employed to determine the mRNA levels of PHD2,VEGF,PDGF,and PDGFR in the renal tissue.Western blot was employed to determine the protein levels of HIF-1α,VEGF,PDGF,and PDGFR in the renal tissue.The results showed that compared with the model group,drug administration lowered the levels of glycosylated serum protein(GSP),aerum creatinine(Scr),and blood urea nitrogen(BUN)in a dose-dependent manner(P<0.05 or P<0.01)and mitigated the pathological changes in the renal tissue.Furthermore,drug administration up-regulated mRNA level of PHD2(P<0.05 or P<0.01),down-regulated the mRNA levels of VEGF,PDGF,and PDGFR(P<0.05 or P<0.01)and the protein levels of HIF-1α,VEGF,PDGF,and PDGFR(P<0.01)in the renal tissue,and increased the rate of PHD2-positive cells(P<0.01).In conclusion,the ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radix effectively alleviated the renal fibrosis in DKD rats by inhibiting the expression of key proteins in the HIF-1α signaling pathway mediated by renal hypoxia and reducing extracellular matrix(ECM)deposition.
ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radixdiabetic kidney diseaserenal hypoxiaextra-cellular matrix(ECM)depositionHIF-1α signaling pathway
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