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Farnesoid X receptor protects against kidney injury in uninephrectomized obese mice


Gai, Zhibo; Gui, Ting; Hiller, Christian; Kullak-Ublick, Gerd A (2015). Farnesoid X receptor protects against kidney injury in uninephrectomized obese mice. Journal of Biological Chemistry:2397-2411.

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 (CHOP), markers of ER stress, was more prominent in the proximal tubules of 15 obese compared with 16 non-obese patients. In mice treated with the FXR agonist obeticholic acid (OCA), 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 OCA treatment. Culturing renal proximal tubular cells with free fatty acid (FFA) and FXR agonists showed that FXR activation protected cells from FFA-induced oxidative stress and ER stress, as denoted by a reduction in the level of ROS 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.

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 (CHOP), markers of ER stress, was more prominent in the proximal tubules of 15 obese compared with 16 non-obese patients. In mice treated with the FXR agonist obeticholic acid (OCA), 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 OCA treatment. Culturing renal proximal tubular cells with free fatty acid (FFA) and FXR agonists showed that FXR activation protected cells from FFA-induced oxidative stress and ER stress, as denoted by a reduction in the level of ROS 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:11 December 2015
Deposited On:19 Feb 2016 13:05
Last Modified:21 Nov 2017 18:23
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:This research was originally published in Journal Name. Gai Z et al. Farnesoid X Receptor Protects against Kidney Injury in Uninephrectomized Obese Mice. The Journal of Biological Chemistry, 2016, 291:2397-2411 © the American Society for Biochemistry and Molecular Biology.
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/jbc.M115.694323
PubMed ID:26655953

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