Esaxerenone inhibits lymphangiogenesis and renal interstitial fibrosis in rats with pregnancy aggravated obstructive nephropathy.

AIM: To explore the mechanisms behind the inhibition of lymphangiogenesis in pregnant rats with obstructive nephropathy and assess the protective effects on kidney function. METHODS: Forty nulliparous female Wi-star rats were randomly assigned to four groups: sham operation, sham operation + pregnancy, model, and Esaxerenone groups, with 10 rats in each group. Renal injury was induced in the model and Esaxerenone groups via unilateral ureteral obstruction (UUO). The other two groups underwent ureteral dissociation without ligation. Nine weeks post-UUO, female rats in the sham operation+pregnancy, model, and Esaxerenone groups were mated with male rats (2:1 ratio) to establish a rat model of obstructive nephropathy during pregnancy. Starting the day after UUO, rats in the Esaxerenone group received Esaxerenone at 1 mg⋅kg-1⋅d-1. On the 18th day of pregnancy, 24-hour urine was collected using metabolic cages. The following day, the rats were sacrificed, serum samples collected, and the contralateral kidney removed. Blood urea nitrogen (BUN) was measured using standard biochemical methods, and endogenous creatinine clearance rate (Ccr) was calculated. Kidney tissue pathology was assessed using HE, Masson, and Sirius red staining. Serum aldosterone levels were determined via ELISA. Immunohistochemistry, real-time PCR, and Western blot were employed to assess mineralo-corticoid receptor (MR) activation, lymphangiogenesis, signaling pathways, and fibrosis-related markers. RESULTS: Renal function tests revealed increased BUN levels and decreased Ccr in the model group (P<0. 01). Pathological examination showed dilated renal tubules, significant collagen deposition, and inflammatory cell infiltration in the model group. ELISA results indicated a significant increase in serum aldosterone levels in the model group (P<0. 01). Immunohisto-chemistry showed enhanced nuclear translocation of MR in the kidneys of the model group post-activation. Western blot and real-time PCR demonstrated a marked increase in neutrophil gelatinase-associated lipocalin (NGAL) expression in the model group (P<0. 01). Additionally, the expression of vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR3 was significantly elevated in the renal tubulointerstitium of the model group, as shown by both immunohistochemistry and real-time PCR (P < 0. 01). The PI3K/Akt signaling pathway was activated in the model group, with significantly increased phosphorylation levels observed primarily in renal tubular epithelial and interstitial cells (P<0. 01). Collagen type III (Col III) expression, primarily in the renal tubulointerstitium, was also significantly upregulated in the model group, consistent with real-time PCR results (P<0. 01). Esaxerenone treatment improved renal function, reduced pathological damage, inhibited aldosterone secretion, and downregulated the expression of MR, NGAL, VEGF-C, VEGFR3, phosphorylated PI3K, phosphorylated Akt, and Col III (P<0. 01). CONCLUSION: Esaxerenone mitigates aldosterone-induced MR activation, modulates the PI3K/Akt signaling pathway, reduces lymphangiogenesis in the contralateral kidney of pregnant rats with obstructive nephropathy, decreases collagen deposition, and delays the progression of renal interstitial fibrosis. [ABSTRACT FROM AUTHOR]