Abstract / Summary
Chronic kidney disease (CKD) is a significant global health burden and a leading cause of death in the United States. Chronic inflammation contributes to fibrosis and CKD progression. Here, we present evidence that a key pro-inflammatory group IVA phospholipase A2 enzyme (cPLA2α) is critical to the development of kidney inflammation and fibrosis and can be targeted pharmacologically to attenuate CKD in animal models. Consistent with a role in human disease, overexpression of cPLA2α is seen in kidneys from patients suffering from CKD, and its expression is inversely correlated with the glomerular filtration rate. Genetic ablation of cPLA2α or inhibition with 1-octadeca-3,6,9,12,15-pentaenylsulfanyl-propan-2-one (AVX002) reduced inflammation and ameliorated renal fibrosis in mouse and rat disease models. In addition, reduced levels of eleven arachidonic acid-derived plasma eicosanoids demonstrated inhibitor effectiveness and specificity. Furthermore, AVX002 dose-dependently reduced kidney fibroblast production of profibrotic, pro-inflammatory components leading to progressive fibrotic kidney failure. In conclusion, our results strongly suggest that inhibition of cPLA2α holds promise as a novel therapeutic strategy for renal fibrosis and chronic kidney disease.