title: PPARgamma agonists do not directly enhance basal or insulin-stimulated Na(+) transport via the epithelial Na(+) channel.
abstract: Selective agonists of peroxisome proliferator-activated receptor gamma (PPARgamma) are anti-diabetic drugs that enhance cellular responsiveness to insulin. However, in some patients, fluid retention, plasma volume expansion, and edema have been observed. It is well established that insulin regulates Na(+) reabsorption via the epithelial sodium channel (ENaC) located in the distal tubule. Therefore, we hypothesized that these agonists may positively modulate insulin-stimulated ENaC activity leading to increased Na(+) reabsorption and fluid retention. Using electrophysiological techniques, dose-response curves for insulin-mediated Na(+) transport in the A6, M-1, and mpkCCD(cl4) cell lines were performed. Each line demonstrated hormone efficacy within physiological concentration ranges and, therefore, can be used to monitor clinically relevant effects of pharmacological agents which may affect electrolyte transport. Immunodetection and quantitative PCR analyses showed that each cell line expresses viable and functional PPARgamma receptors. Despite this finding, two PPARgamma agonists, pioglitazone and GW7845 did not directly enhance basal or insulin-stimulated Na(+) flux via ENaC, as shown by electrophysiological methodologies. These studies provide important results, which eliminate insulin-mediated ENaC activation as a candidate mechanism underlying the fluid retention observed with PPARgamma agonist use.
authors.affiliation: Department of Biology, Indiana University Purdue University at Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Charity
authors.initials: C
authors.lastname: Nofziger
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Michael Anne
authors.initials: MA
authors.lastname: Shane
authors.forename: Chari D
authors.initials: CD
authors.lastname: Smith
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Brown
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Blazer-Yost
mesh_terms: D000818:Animals; D002460:Cell Line; D004487:Edema / Q000139:chemically induced; D053503:Epithelial Sodium Channels; D007004:Hypoglycemic Agents / Q000009:adverse effects; D007328:Insulin / Q000502:physiology*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D053503:Epithelial Sodium Channels; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D015222:Sodium Channels; D012964:Sodium