PPARgamma agonists inhibit vasopressin-mediated anion transport in the MDCK-C7 cell line.
PPARgamma agonists are synthetic ligands for the peroxisome proliferator-activated receptor-gamma (PPARgamma). These agents have insulin-sensitizing properties but can cause fluid retention, thereby limiting their usefulness in patients at risk for cardiovascular disease. The side effect etiology is unknown, but the nature of presentation suggests modulation of renal salt and water homeostasis. In a well-characterized cell culture model of the principal cell type [Madin-Darby canine kidney (MDCK)-C7], PPARgamma agonists inhibit vasopressin-stimulated Cl(-) secretion with agonist dose-response relationships that mirror receptor transactivation profiles. Analyses of the components of the vasopressin-stimulated intracellular signaling pathway indicated no PPARgamma agonist-induced changes in basolateral membrane conductances, intracellular cAMP, protein kinase A, or total cellular adenine nucleotides. The PPARgamma agonist-induced decrease in anion secretion is the result of decreased mRNA of the final effector in the pathway, the apically located cystic fibrosis transmembrane regulator (CFTR). These data showing that CFTR is a target for PPARgamma agonists may provide new insights into the physiology of PPARgamma agonist-induced fluid retention.
Nofziger
Charity
C
Department of Biology, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202, USA.
Brown
Kathleen K
KK
Smith
Chari D
CD
Harrington
Wallace
W
Murray
David
D
Bisi
John
J
Ashton
Thalia T
TT
Maurio
Frank P
FP
Kalsi
Kameljit
K
West
T Aaron
TA
Baines
Deborah
D
Blazer-Yost
Bonnie L
BL
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D053503:Epithelial Sodium Channels / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008024:Ligands; D023421:Models, Animal; D010080:Oxazoles / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014667:Vasopressins / Q000494:pharmacology*
D002712:Chlorides; D053503:Epithelial Sodium Channels; D008024:Ligands; D010080:Oxazoles; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014667:Vasopressins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C422415:farglitazar; D014443:Tyrosine; D000077205:Pioglitazone