title: Farnesoid X Receptor Protects against Kidney Injury in Uninephrectomized Obese Mice.
abstract: Activation of the farnesoid X receptor (FXR) has indicated a therapeutic potential for this nuclear bile acid receptor in the prevention of diabetic nephropathy and obesity-induced renal damage. Here, we investigated the protective role of FXR against kidney damage induced by obesity in mice that had undergone uninephrectomy, a model resembling the clinical situation of kidney donation by obese individuals. Mice fed a high-fat diet developed the core features of metabolic syndrome, with subsequent renal lipid accumulation and renal injury, including glomerulosclerosis, interstitial fibrosis, and albuminuria. The effects were accentuated by uninephrectomy. In human renal biopsies, staining of 4-hydroxynonenal (4-HNE), glucose-regulated protein 78 (Grp78), and C/EBP-homologous protein, markers of endoplasmic reticulum stress, was more prominent in the proximal tubules of 15 obese patients compared with 16 non-obese patients. In mice treated with the FXR agonist obeticholic acid, renal injury, renal lipid accumulation, apoptosis, and changes in lipid peroxidation were attenuated. Moreover, disturbed mitochondrial function was ameliorated and the mitochondrial respiratory chain recovered following obeticholic acid treatment. Culturing renal proximal tubular cells with free fatty acid and FXR agonists showed that FXR activation protected cells from free fatty acid-induced oxidative stress and endoplasmic reticulum stress, as denoted by a reduction in the level of reactive oxygen species staining and Grp78 immunostaining, respectively. Several genes involved in glutathione metabolism were induced by FXR activation in the remnant kidney, which was consistent with a decreased glutathione disulfide/glutathione ratio. In summary, FXR activation maintains endogenous glutathione homeostasis and protects the kidney in uninephrectomized mice from obesity-induced injury.
authors.affiliation: From the Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland and.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Gai
authors.affiliation: the Department of Nephrology, Hypertension, and Clinical Pharmacology, Inselspital, CH-3010 Bern, Switzerland.
authors.forename: Ting
authors.initials: T
authors.lastname: Gui
authors.affiliation: From the Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland and.
authors.forename: Christian
authors.initials: C
authors.lastname: Hiller
authors.affiliation: From the Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland and gerd.kullak@usz.ch.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D059305:Diet, High-Fat; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005230:Fatty Acids, Nonesterified / Q000737:chemistry; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000293:injuries* / Q000503:physiopathology; D007674:Kidney Diseases / Q000378:metabolism*; D007684:Kidney Tubules / Q000473:pathology; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D009392:Nephrectomy; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000447:Aldehydes; D001647:Bile Acids and Salts; D022762:CCAAT-Enhancer-Binding Proteins; D002635:Chenodeoxycholic Acid; D000091342:Endoplasmic Reticulum Chaperone BiP; D005230:Fatty Acids, Nonesterified; D005978:Glutathione; D006360:Heat-Shock Proteins; D008055:Lipids; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C530718:CEBPA protein, mouse; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C464660:obeticholic acid; C027576:4-hydroxy-2-nonenal
keywords: INT-747; anion transport; bile acid; endoplasmic reticulum (ER) stress; fatty liver disease; kidney donor; kidney metabolism; nonalcoholic steatohepatitis; nuclear receptor; oxidative stress