Authors: Charity Nofziger Lihong Chen Michael Anne Shane Chari D Smith Kathleen K Brown Bonnie L BlazerYost
Publish Date: 2005/09/17
Volume: 451, Issue: 3, Pages: 445-453
Abstract
Selective agonists of peroxisome proliferatoractivated receptor gamma PPARγ are antidiabetic 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 insulinstimulated ENaC activity leading to increased Na+ reabsorption and fluid retention Using electrophysiological techniques dose–response curves for insulinmediated Na+ transport in the A6 M1 and mpkCCDcl4 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 PPARγ receptors Despite this finding two PPARγ agonists pioglitazone and GW7845 did not directly enhance basal or insulinstimulated Na+ flux via ENaC as shown by electrophysiological methodologies These studies provide important results which eliminate insulinmediated ENaC activation as a candidate mechanism underlying the fluid retention observed with PPARγ agonist use
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