Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis

Exp Clin Endocrinol Diabetes. 2008 Jun;116(6):315-25. doi: 10.1055/s-2008-1042429.

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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chromosome Mapping
  • Gene Expression Regulation, Enzymologic
  • Genome
  • Kidney / enzymology*
  • Male
  • Obesity / drug therapy*
  • Obesity / enzymology
  • Obesity / genetics*
  • Oligonucleotide Array Sequence Analysis*
  • Peptidyl-Dipeptidase A / genetics*
  • Rats
  • Rats, Zucker
  • Rosiglitazone
  • Stearoyl-CoA Desaturase / genetics*
  • Thiazolidinediones / therapeutic use*

Substances

  • Thiazolidinediones
  • Rosiglitazone
  • Stearoyl-CoA Desaturase
  • Peptidyl-Dipeptidase A