Xaliproden improves diabetic kidney disease through JNK-mediated renal tubular protection

Diabetic kidney disease (DKD) is a major diabetic complication and the primary global cause of end-stage renal disease. Hyperglycemia triggers multiple pathological signaling pathways and ultimately leads to structural alterations and functional decline in the kidney. Xaliproden is a 5-HT₁A receptor agonist originally developed for its neuroprotective effects; however, its impacts on renal disease remain unknown. The objective of this study is to investigate the therapeutic promise of xaliproden in DKD. Db/db mice were used in a mouse model of DKD in vivo, and high glucose (HG)-stimulated renal tubular epithelial cells were employed to explore the mechanistic insights in vitro. In DKD mice, xaliproden exerted reno-protective effects, as evidenced by reduced serum levels of blood urea nitrogen and creatinine as well as decreased urinary albumin-to-creatinine ratios. Furthermore, xaliproden markedly attenuated DKD-induced renal tubular injury, as indicated by decreased tubular injury score and decreased collagen deposition in kidney sections, accompanied by a reduction in inflammatory, apoptotic, and fibrotic proteins in renal tissues. In HG-stimulated renal tubular epithelial cells, xaliproden reduced the expression of inflammatory, apoptotic, and fibrotic proteins, including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, cleaved caspase-3, cleaved poly-ADP-ribose polymerases, transforming growth factor β, p-Smad2/3, and collagen 1. These effects were mediated through downregulation of the c-Jun N-terminal kinase/p65/c-Jun signaling pathway. In conclusion, these findings demonstrate that xaliproden confers reno-protective effects by mitigating renal tubular epithelial cell damage and improving renal function in DKD, suggesting its potential as a therapeutic option for DKD.