You-Gui-Yin improved the reproductive dysfunction of male rats with chronic kidney disease via regulating the HIF1α-STAT5 pathway

Ethnopharmacological relevance: You-Gui-Yin (YGY) is a famous Chinese traditional medicine compound that has been used to treat renal function diseases for more than 300 years. It is recorded in Jing Yue Quanshu, which was written by a famous medical scientist named Jiebing Zhang in the Ming Dynasty. Aim of the study: Reproductive dysfunction is one of the most serious complications of chronic kidney disease (CKD). The aim of this study was to observe the effect of You-Gui-Yin (YGY) on reproductive dysfunction of male rats with adenine-induced CKD and to determine if any effects occurred via regulation of the HIF1 alpha-STAT5 pathway. Materials and methods: UPLC-Q-TOF-MS was used to detect the main medicinal components and conduct quality control of YGY. A total of 60 rats were randomly divided into 2 groups: the NC group (10 rats) and the CKD model group (50 rats). The CKD model rats was established by administration of adenine 150 mg kg(-1) orally for 14 days. After that, the CKD rats were randomly divided into 5 groups: the CKD group, YGY (10 g kg(-1) group, 20 g kg(-1) group, 40 g kg(-1) group) and the GUI-LU-ER-XIAN-JIAO (GL) 10 g kg(-1) group with 10 rats in each group. From the 15th day to the 45th day rats were given 150 mg kg(-1) adenine orally every other day to maintain the model (except in the NC group). The YGY groups and the GL group were orally administered the relevant drug once per day for 30 days. The NC group and the CKD group were orally administered an equal volume of normal saline for 30 days. On the 45th day, the rats' sexual behavior index was tested. On the 46th day, the rats were sacrificed. Biochemical indexes, histopathological changes of the kidneys and testes, sperm morphology, sperm abnormality rate, and key proteins in the HIF1 alpha-STAT5 pathway in the kidney and testis were detected. Results: Thirteen components in the YGY extract were identified by UPLC-Q-TOF-MS for quality control of the YGY extract. The results of the biochemical and physiological tests validated the success of inducing CKD accompanied by reproductive dysfunction in rats. YGY significantly retarded the CKD progression and improved the hormone levels of male CKD rats. Sexual behavior tests showed YGY can significantly improve CKD rats' sexual function. In addition, the pathological changes of the kidney and testis, sperm abnormality rate and sperm morphological abnormalities of the CKD rats were reduced by YGY. Furthermore, decreased expression of HIF1 alpha and EPO, and increased expression of p-EPOR (Tyr368), p-JAK2 (Tyr570) and p-STAT5 (Ser725) were observed in the kidney and the testis of the CKD rats. The YGY extract dramatically increased the expression of HIF1 alpha and EPO, and decreased the expression of p-EPOR (Tyr368), p-JAK2 (Tyr570) and p-STAT5 (Ser725) to regulate key proteins in the HIF1 alpha-STAT5 pathway of the kidney and testis. Conclusions: YGY has obvious reversal effects on the abnormal symptoms of adenine-induced CKD and the abnormal symptoms of rats with hypothyroidism and male reproductive hypotension. Its mechanism is related to its ability to regulate the HIF1 alpha-STAT5 pathway.