Esaxerenone regulates NCC/HIF-1α signaling pathway to inhibit lymphangiogenesis and alleviates renal fibrosis in pregnant rats with obstructive nephropathy

AimTo investigate the protective effects of esaxerenone on obstructive nephropathy combined with pregnancy in rats through the regulation of the Na+/Cl- cotransporter (NCC)/hypoxia-inducible factor 1 alpha (HIF-1α) signaling pathway and its mechanism in renal fibrosis.MethodsFemale Wistar rats aged 5-6 weeks were randomly divided into five groups: sham surgery group, sham surgery+pregnancy group, unilateral ureteral obstruction (UUO) group, UUO+pregnancy model group, and esaxerenone treatment group. The model of obstructive nephropathy combined with pregnancy was established. Rats in the esaxerenone treatment group were administered esaxerenone at a dose of 1 mg·kg-1·d-1 starting from the second day after surgery. Urine was collected for 24 h on the 19th day, serum was collected the following day, and the obstructed contralateral kidney was excised. Biochemical and molecular level changes in each group were detected by using HE staining, Sirius red staining, ELISA, immunohistochemistry, immunofluorescence, Real-time PCR, and Western blot analysis.ResultsPathological results showed that rats in the model group had significant renal tubular dilation and collagen fiber deposition. ELISA results indicated a significant increase in aldosterone levels in the model group. Immunohistochemistry, immunofluorescence, PCR, and Western blot analyses revealed that, compared with the sham surgery group, the model group had significantly elevated levels of MR, SGK-1, VEGF-C, VEGFR3, Prox-1, NCC, HIF-1α, and collagen I. After esaxerenone treatment, these indicators were significantly downregulated.ConclusionsEsaxerenone effectively alleviates the progression of renal fibrosis by blocking mineralocorticoid receptors, reducing sodium and water retention, and inhibiting hypoxia, thus suppressing lymphangiogenesis.