Abstract
Lysophosphatidic acid (LPA) is a biologically active lysophospholipid, and acts on six types of LPA receptors (LPA1-LPA6). LPA-LPA1 signaling has been suggested as a therapeutic target for inflammatory and fibrotic disorders, including renal fibrosis. In this study, we investigated the effects of AM095, an LPA1 selective antagonist, on hypertensive renal injury in Dahl-Iwai salt-sensitive (DS) rats. We evaluated the preventive as well as therapeutic efficacy of AM095 in reducing proteinuria, and improving impaired renal function and renal fibrosis in the hypertensive DS rat. Preventive administration of AM095 suppressed proteinuria, renal function impairment and renal fibrosis in the hypertensive DS rats. In addition, therapeutic administration of AM095 reduced the levels of proximal tubular injury markers and suppressed renal fibrosis. Furthermore, combined administration of AM095 with an angiotensin-converting enzyme (ACE) inhibitor reduced the levels of proximal tubular injury markers and kidney weight increase, and suppressed renal fibrosis more effectively than administration of either agent alone, independent of the antihypertensive effect of the ACE inhibitor. These results provide the first evidence of the potential efficacy of LPA1 antagonist in suppressing renal injury in hypertensive DS rats, suggesting the promise of LPA1 antagonists as a novel therapeutic option for hypertensive renal injury.