Gemigliptin Ameliorates Renal Fibrosis By Attenuating Nlrp3-Mediated Inflammation In A Murine Model

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although activation of NOD-like receptor protein 3 (NLRP3) inflammasome has been reported to play an important role in the progression of renal fibrosis, the relevance of DDP-4 inhibitor to NLRP3 inflammation on its ameliorating effect on renal fibrosis has not been fully studied. The aim of this study was to investigate the association of renoprotective effect of gemigliptin with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis. Methods: We evaluated the effects of gemigliptin on renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO) in mice. We quantitated levels of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment through immunohistochemical and western blot analysis. In human kidney tubular epithelial HK-2 cells, we defined the effect of gemigliptin on TGF-β-stimulated production of profibrotic proteins. Results: We observed that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, caspase-1, ASC, and IL-1β, which had all been clearly increased by UUO. Furthermore, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin. treatment. Additionally, gemigliptin treatment attenuated phosphorylated NF-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells. Conclusion: The present study demonstrated that the renoprotective effect of gemigliptin is associated with amelioration of NLRP3 inflammasome. Disclosure G. Jung: None. Y. Choi: None. J. Seo: None. S. Park: None. N. Kim: None. M. Kim: None. J. Kim: None. I. Lee: Board Member; Self; NovMetapharm Co, Inc. K. Park: None. Funding National Research Foundation of Korea