title: Uninephrectomy augments the effects of high fat diet induced obesity on gene expression in mouse kidney.
abstract: Obesity has been reported as an independent risk factor for chronic kidney disease, leading to glomerulosclerosis and renal insufficiency. To assess the relationship between a reduced nephron number and a particular susceptibility to obesity-induced renal damage, mice underwent uninephrectomy (UNX) followed by either normal chow or high-fat diet (HFD) and were compared with sham-operated control mice. After 20 weeks of dietary intervention, HFD-fed control mice presented characteristic features of progressive nephropathy, including albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. These changes were more pronounced in HFD-fed mice that had undergone uninephrectomy. Analysis of gene expression in mouse kidney by whole genome microarrays indicated that high fat diet led to more changes in gene expression than uninephrectomy. HFD affected mainly genes involved in lipid metabolism and transport, whereas the combination of UNX and HFD additionally altered the expression of genes belonging to cytoskeleton remodeling, fibrosis and hypoxia pathways. Canonical pathway analyses identified the farnesoid X receptor (FXR) as a potential key mediator for the observed changes in gene expression associated with UNX-HFD. In conclusion, HFD-induced kidney damage is more pronounced following uninephrectomy and is associated with changes in gene expression that implicate FXR as a central regulatory pathway.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland. Electronic address: zhibo.gai@usz.ch.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Gai
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland. Electronic address: christian.hiller@usz.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Hiller
authors.affiliation: Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland; Children's Research Centre, University Children's Hospital, Zurich, Switzerland; Zurich Centre for Integrative Human Physiology, University of Zurich, Switzerland. Electronic address: siewhung.chin@usz.ch.
authors.forename: Siew Hung
authors.initials: SH
authors.lastname: Chin
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland. Electronic address: lia.hofstetter@usz.ch.
authors.forename: Lia
authors.initials: L
authors.lastname: Hofstetter
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland. Electronic address: bruno.stieger@uzh.ch.
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.affiliation: Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland; Children's Research Centre, University Children's Hospital, Zurich, Switzerland; Zurich Centre for Integrative Human Physiology, University of Zurich, Switzerland. Electronic address: daniel.konrad@kispi.uzh.ch.
authors.forename: Daniel
authors.initials: D
authors.lastname: Konrad
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland; Zurich Centre for Integrative Human Physiology, University of Zurich, Switzerland. Electronic address: gerd.kullak@usz.ch.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005355:Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy / Q000009:adverse effects*; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger
keywords: BMP pathway; Bile acids; Gene regulation; Nuclear receptor; Organic anion transporter; Wnt signaling