Basic ResearchActivation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic NephropathyTachibana, Hiromi*; Ogawa, Daisuke*,†; Matsushita, Yuichi*; Bruemmer, Dennis‡; Wada, Jun*; Teshigawara, Sanae*; Eguchi, Jun*; Sato-Horiguchi, Chikage*,†; Uchida, Haruhito Adam*; Shikata, Kenichi*,§; Makino, Hirofumi* Author Information * Departments of *Medicine and Clinical Science and †Diabetic Nephropathy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ‡ Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, Kentucky; and § Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan Correspondence: Dr. Daisuke Ogawa, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Email: [email protected] Received January 13, 2012 Accepted July 5, 2012 Journal of the American Society of Nephrology 23(11):p 1835-1846, November 2012. | DOI: 10.1681/ASN.2012010022 Buy Metrics Abstract Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1–dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy. Copyright © 2012 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.