title: 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.
authors.affiliation: 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.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tachibana
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Sanae
authors.initials: S
authors.lastname: Teshigawara
authors.forename: Jun
authors.initials: J
authors.lastname: Eguchi
authors.forename: Chikage
authors.initials: C
authors.lastname: Sato-Horiguchi
authors.forename: Haruhito Adam
authors.initials: HA
authors.lastname: Uchida
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D053495:Osteopontin; D012333:RNA, Messenger; D013449:Sulfonamides; D018808:Transcription Factor AP-1; C506896:Spp1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides