title: Lipid droplet accumulation is associated with an increase in hyperglycemia-induced renal damage: prevention by liver X receptors.
abstract: Dyslipidemia is a frequent component of the metabolic disorder of diabetic patients contributing to organ damage. Herein, in low-density lipoprotein receptor-deficient hyperlipidemic and streptozotozin-induced diabetic mice, hyperglycemia and hyperlipidemia acted reciprocally, accentuating renal injury and altering renal function. In hyperglycemic-hyperlipidemic kidneys, the accumulation of Tip47-positive lipid droplets in glomeruli, tubular epithelia, and macrophages was accompanied by the concomitant presence of the oxidative stress markers xanthine oxidoreductase and nitrotyrosine, findings that could also be evidenced in renal biopsy samples of diabetic patients. As liver X receptors (LXRα,β) regulate genes linked to lipid and carbohydrate homeostasis and inhibit inflammatory gene expression in macrophages, the effects of systemic and macrophage-specific LXR activation were analyzed on renal damage in hyperlipidemic-hyperglycemic mice. LXR stimulation by GW3965 up-regulated genes involved in cholesterol efflux and down-regulated proinflammatory/profibrotic cytokines, inhibiting the pathomorphology of diabetic nephropathy, renal lipid accumulation, and improving renal function. Xanthine oxidoreductase and nitrotyrosine levels were reduced. In macrophages, GW3965 or LXRα overexpression significantly suppressed glycated or acetylated low-density lipoprotein-induced cytokines and reactive oxygen species. Specifically, in mice, transgenic expression of LXRα in macrophages significantly ameliorated hyperlipidemic-hyperglycemic nephropathy. The results demonstrate the presence of lipid droplet-induced oxidative mechanisms and the pathophysiologic role of macrophages in diabetic kidneys and indicate the potent regulatory role of LXRs in preventing renal damage in diabetes.
authors: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. e.kiss@dkfz.de
authors: Eva
authors: E
authors: Kiss
authors: Bettina
authors: B
authors: Kränzlin
authors: Katja
authors: K
authors: Wagenblaβ
authors: Mahnaz
authors: M
authors: Bonrouhi
authors: Joachim
authors: J
authors: Thiery
authors: Elisabeth
authors: E
authors: Gröne
authors: Viola
authors: V
authors: Nordström
authors: Daniel
authors: D
authors: Teupser
authors: Norbert
authors: N
authors: Gretz
authors: Ernst
authors: E
authors: Malle
authors: Hermann-Josef
authors: HJ
authors: Gröne
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D005355:Fibrosis; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D007677:Kidney Function Tests; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
chemical_list: D001565:Benzoates; D001596:Benzylamines; D016207:Cytokines; C473027:GW 3965; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors