title: Coordinate regulation between the nuclear receptor peroxisome proliferator-activated receptor-γ and cyclooxygenase-2 in renal epithelial cells.
abstract: The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors involved in lipid metabolism and glucose utilization, in cell growth, differentiation and apoptosis, and in the regulation of pro-inflammatory genes expression such as cyclooxygenase-2 (COX-2). PPARγ is the main isoform in the renal inner medulla where it is believed to possess nephroprotective actions. In this kidney zone, COX-2 acts as an osmoprotective gene and its expression is modulated by changes in interstitial osmolarity. In the present work we evaluated whether hyperosmolar-induced COX-2 expression is modulated by PPARγ in renal epithelial cells MDCK subjected to high NaCl medium. The results presented herein show that ligand-activated PPARγ repressed COX-2 expression. But more important, the present findings show that hyperosmolar medium decreased PPARγ protein and increases the PPARγ phosphorylated form, which is inactive. ERK1/2 and p38 activation precedes PPARγ disappearance and induced-COX-2 expression. Therefore, the decrease in PPARγ expression is required for hyperosmotic induction of COX-2. We also found that PGE2, the main product of COX-2 in MDCK cells, induced these changes in PPARγ protein. Our results may alert on the long term use of thiazolidinediones (TZD) since they could affect renal medullary function that depends on COX-2 for cellular protection against osmotic stress.
authors.affiliation: Department of Biological Sciences, School of Pharmacy and Biochemistry, University of Buenos Aires Ciudad Autónoma de Buenos Aires C1113AAD, Argentina; IQUIFIB-CONICET, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
authors.forename: Cecilia I
authors.initials: CI
authors.lastname: Casali
authors.affiliation: Department of Biological Sciences, School of Pharmacy and Biochemistry, University of Buenos Aires Ciudad Autónoma de Buenos Aires C1113AAD, Argentina; IQUIFIB-CONICET, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
authors.forename: Karen
authors.initials: K
authors.lastname: Weber
authors.affiliation: Department of Biological Sciences, School of Pharmacy and Biochemistry, University of Buenos Aires Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
authors.forename: Daniela
authors.initials: D
authors.lastname: Faggionato
authors.affiliation: Department of Biological Sciences, School of Pharmacy and Biochemistry, University of Buenos Aires Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
authors.forename: Emanuel Morel
authors.initials: EM
authors.lastname: Gómez
authors.affiliation: Department of Biological Sciences, School of Pharmacy and Biochemistry, University of Buenos Aires Ciudad Autónoma de Buenos Aires C1113AAD, Argentina; IQUIFIB-CONICET, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina. Electronic address: fertome@ffyb.uba.ar.
authors.forename: María C Fernández
authors.initials: MC
authors.lastname: Tome
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D017931:DNA Primers; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000201:enzymology; D007668:Kidney / Q000166:cytology / Q000201:enzymology*; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D012965:Sodium Chloride / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D017931:DNA Primers; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D012965:Sodium Chloride; D051546:Cyclooxygenase 2; D011494:Protein Kinases; D015232:Dinoprostone; D015230:Prostaglandin D2
keywords: Cyclooxygenase-2 (COX-2); Hyperosmolarity; Nephroprotection; Peroxisome proliferator-activated receptor gamma (PPARγ); Thiazolidinediones (TZD)