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

Zhang MZ, Wang X, Yang H, Fogo AB, Murphy BJ, Kaltenbach R, Cheng P, Zinker B, Harris RC
J Am Soc Nephrol. 2017 28 (11): 3300-3311

PMID: 28739650 · PMCID: PMC5661289 · DOI:10.1681/ASN.2017010107

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 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 (<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, -smooth muscle actin, connective tissue growth factor, collagen I, and TGF-; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, =4; at 20 weeks: 364±18 with vehicle, =7, and 536±12 with LPAR inhibition, =7; <0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.

Copyright © 2017 by the American Society of Nephrology.

MeSH Terms (6)

Animals Diabetes Mellitus, Type 2 Diabetic Nephropathies Disease Models, Animal Mice Receptors, Lysophosphatidic Acid

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