title: Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis.
abstract: Thiazolidinediones increase tissue insulin sensitivity and are protective against worsening of nephropathy and hypertension in diabetes. Mechanisms underlying protection at the renal level likely involve a variety of unknown changes in gene expression. We examined kidney gene expression in obese and lean Zucker rats in response to rosiglitazone (Avandia), a peroxisome proliferator activated receptor (gamma-subtype) agonist. Lean and obese Zucker rats were treated with either control chow or chow with added rosiglitazone (3 mg/kg x bw) for 12 weeks (n = 3/group). Total kidney mRNA expression was evaluated using the Affymetrix Rat Genome 230 2.0 GeneChip. 903 probe sets were significantly (P < 0.05) altered with at least 1.5-fold changes between groups. In untreated obese rats, 300 probe sets were increased and 244 decreased, relative to lean. Increased genes included the beta-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter, and aquaporin 3. Decreased genes included angiotensin converting enzyme, type 1 (ACE1). FatiGO analysis showed that the highest number of altered genes between lean and obese belonged to the categories: ion binding, hydrolase activity, and protein binding. RGZ increased expression of uncoupling protein 1 (UCP1), CD36, and fatty acid binding protein 4 (FAbp4) in both lean and obese rats. In obese rats, 33 genes were normalized by RGZ (no longer different from lean) including ACE1, fatty acid synthase (Fasn), and stearoyl-coenzyme A desaturase (SCD1). Ingenuity Pathways System analysis of genes upregulated by RGZ in obese rats revealed two major nodes affected: PPAR-gamma and tumor necrosis factor alpha (TNF-alpha).
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington, DC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Song
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.forename: H W
authors.initials: HW
authors.lastname: Ressom
authors.forename: S
authors.initials: S
authors.lastname: Tiwari
authors.forename: C M
authors.initials: CM
authors.lastname: Ecelbarger
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D015971:Gene Expression Regulation, Enzymologic; D016678:Genome; D007668:Kidney / Q000201:enzymology*; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D013230:Stearoyl-CoA Desaturase / Q000235:genetics*; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013230:Stearoyl-CoA Desaturase; D007703:Peptidyl-Dipeptidase A