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Activation of liver X receptor inhibits osteopontin and ameliorates diabetic nephropathy.

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.
AuthorsHiromi Tachibana, Daisuke Ogawa, Yuichi Matsushita, Dennis Bruemmer, Jun Wada, Sanae Teshigawara, Jun Eguchi, Chikage Sato-Horiguchi, Haruhito Adam Uchida, Kenichi Shikata, Hirofumi Makino
JournalJournal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 23 Issue 11 Pg. 1835-46 (Nov 2012) ISSN: 1533-3450 [Electronic] United States
PMID23085633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Hydrocarbons, Fluorinated
  • Inflammation Mediators
  • Ligands
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • RNA, Messenger
  • Spp1 protein, mouse
  • Sulfonamides
  • T0901317
  • Transcription Factor AP-1
  • Osteopontin
Topics
  • Animals
  • Cell Line
  • Diabetes Mellitus, Experimental (drug therapy, genetics, metabolism)
  • Diabetic Nephropathies (drug therapy, genetics, metabolism, pathology)
  • Gene Expression (drug effects)
  • Hydrocarbons, Fluorinated (pharmacology)
  • Inflammation Mediators (metabolism)
  • Kidney (drug effects, metabolism, pathology)
  • Ligands
  • Liver X Receptors
  • Macrophages (drug effects, pathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Orphan Nuclear Receptors (agonists)
  • Osteopontin (antagonists & inhibitors, genetics, metabolism)
  • Promoter Regions, Genetic
  • RNA, Messenger (genetics, metabolism)
  • Sulfonamides (pharmacology)
  • Transcription Factor AP-1 (metabolism)

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