Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model

Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA–LPAR signaling has been implicated in development of fibrosis. However, the role of LPA–LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout db/db mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups ( P α -smooth muscle actin, connective tissue growth factor, collagen I, and TGF- β ; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, n =4; at 20 weeks: 364±18 with vehicle, n =7, and 536±12 with LPAR inhibition, n =7; P