Esculetin alleviates IgA nephropathy in rats by improving intestinal mucosal function through the IL-17/NF-κB...

Based on the "gut-kidney axis" theory, the disruption of the intestinal barrier function has been identified as a contributor to the occurrence and development of IgA nephropathy (IgAN). Esculetin, as a bioactive compound isolated from the medicinal herb Cortex Fraxin, has been demonstrated to exert protective effects against kidney and intestinal injury. Our study aimed to evaluate the effects of esculetin on IgAN progression and the associated mechanism. Sprague-Dawley rats were treated with bovine serum albumin (BSA), lipopolysaccharide (LPS), and carbon tetrachloride (CCL4) to establish the IgAN animal models, during which period the rats were orally administrated with esculetin (100 mg/kg) once a day for 12 weeks. After collecting 24-h urine samples to detect proteinuria levels, the rats were sacrificed and blood samples were harvested to examine serum blood urea nitrogen (BUN), serum creatinine (SCr), and serum IgA, IL-17, and pro-inflammatory cytokine levels. Kidney and intestinal tissues were subjected to hematoxylin-eosin (HE), periodic acid-Schiff (PAS), and alcian blue-periodic acid-Schiff (AB/PAS) staining, immunofluorescent and immunohistochemical staining, RT-qPCR, and western blotting to determine histopathological changes, IgA glomerular deposition, and the expression of tight junction proteins, IL-17, and NF-κB pathway-related molecules. Esculetin administration attenuated 24-h proteinuria, BUN, and SCr levels, alleviated renal pathological injury, inhibited IgA glomerular deposition, and decreased serum IgA and pro-inflammatory cytokines levels in IgAN rats. Furthermore, esculetin mitigated pathological injury, increased the number of mucin-producing goblet cells, and enhanced tight junction protein expression in the intestinal tissues of IgAN rats. Esculetin downregulated serum, renal, and intestinal levels of IL-17 as well as renal and intestinal levels of p-NF-κB p65 and p-IκBα in IgAN rats. Esculetin exerts both renal protection and intestinal mucosal barrier protection effect in IgAN rat models by inactivating the IL-17/NF-κB signaling.