Renoprotective effects of novel interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 through anti-inflammatory action in 5/6 nephrectomized rats

Renal inflammation is a final common pathway of chronic kidney disease (CKD), and its progression can be used to effectively gauge the degree of renal dysfunction. Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4) has been reported to be a pivotal molecule for IL-1 receptor- and Toll-like receptor-induced signaling and activation of proinflammatory mediators. In this study, we hypothesized that if inflammation plays a key role in renal failure, then the anti-inflammatory effect of IRAK-4 inhibitor should be effective in improving CKD. To determine its pharmacological potency, we investigated the renoprotective properties of the novel IRAK-4 inhibitor AS2444697 (N-[3-carbamoyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]-2-(2-methylpyridin-4-yl)-1,3-oxazole-4-carboxamide hydrochloride (1:1)) in 5/6 nephrectomized (Nx) rats, a model of CKD. Six weeks' repeated administration of AS2444697 (0.3-3 mg/kg, twice daily) dose-dependently and significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and interstitial fibrosis without affecting the blood pressure. In addition, AS2444697 showed beneficial effects on renal function as demonstrated by the decrease in levels of plasma creatinine and blood urea nitrogen and attenuation of decline in creatinine clearance. 5/6 Nx rats exhibited low-grade inflammation as evidenced by increased renal mRNA expression and plasma levels of proinflammatory cytokines (IL-1 beta, IL-6, TNF-alpha, and MCP-1) and C-reactive protein as a marker of systemic inflammation. AS2444697 significantly reduced or showed a decreasing trend in expression and levels of these inflammatory parameters. These results suggest that AS2444697 suppresses the progression of chronic renal failure via anti-inflammatory action and may therefore be potentially useful in treating CKD patients.