obeticholic-acid and Kidney-Diseases

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.

Topics: Aldehydes; Animals; Bile Acids and Salts; CCAAT-Enhancer-Binding Proteins; Chenodeoxycholic Acid; Diet, High-Fat; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Fatty Acids, Nonesterified; Female; Glutathione; Heat-Shock Proteins; Humans; Kidney; Kidney Diseases; Kidney Tubules; Lipid Metabolism; Lipid Peroxidation; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Nephrectomy; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Reactive Oxygen Species; Receptors, Cytoplasmic and Nuclear

Vascular calcification is highly associated with cardiovascular morbidity and mortality, especially in patients with chronic kidney disease. The nuclear receptor farnesoid X receptor (FXR) has been implicated in the control of lipid, carbohydrate and bile acid metabolism in several cell types. Although recent studies have shown that FXR is also expressed in vascular smooth muscle cells, its physiological role in vasculature tissue remains obscure.. Here, we have examined the role of FXR in vascular calcification.. The FXR gene, a bile acid nuclear receptor, was highly induced during osteogenic differentiation of bovine calcifying vascular cells (CVCs) and in the aorta of apolipoprotein (Apo)E(-/-) mice with chronic kidney disease which are common tissue culture and mouse model, respectively, for aortic calcification. FXR activation by a synthetic FXR agonist, 6alpha-ethyl chenodeoxycholic acid (INT-747) inhibited phosphate induced-mineralization and triglyceride accumulation in CVCs. FXR dominant negative expression augmented mineralization of CVCs and blocked the anticalcific effect of INT-747 whereas VP16FXR that is a constitutively active form reduced mineralization of CVCs. INT-747 treatment also increased phosphorylated c-Jun N-terminal kinase (JNK). SP600125 (specific JNK inhibitor) significantly induced mineralization of CVCs and alkaline phosphatase expression, suggesting that the anticalcific effect of INT-747 is attributable to JNK activation. We also found that INT-747 ameliorates chronic kidney disease induced-vascular calcification in 5/6 nephrectomized ApoE(-/-) mice without affecting the development of atherosclerosis.. These observations provide direct evidence that FXR is a key signaling component in regulation of vascular osteogenic differentiation and, thus representing a promising target for the treatment of vascular calcification.

Topics: Animals; Aorta; Apolipoproteins E; Calcinosis; Cattle; Cell Differentiation; Cells, Cultured; Chenodeoxycholic Acid; Chronic Disease; Disease Models, Animal; Kidney Diseases; Male; Mice; Mice, Knockout; Osteogenesis; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Triglycerides; Vascular Diseases