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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 8, 2004; DOI: 10.1124/jpet.104.074088

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Received for publication July 15, 2004.
Revised September 8, 2004.
Accepted for publication October 7, 2004.

GI262570, a PPAR{gamma} agonist, changes electrolytes and water reabsorption from the distal nephron in rats

Lihong Chen 1*, Baichun Yang 2, Judi A McNulty 3, Lisa G Clifton 1, Jane G Binz 1, Angela M Grimes 1, Jay C Strum 1, W Wallace Harrington 1, Zibin Chen 1, Thomas W Balon 1, Stephen A Stimpson 1, Kathleen K Brown 1

1 GlaxoSmithKline, Inc. 2 GlaxoSmithKline 3 GalxoSmithKline, Inc.

* Address correspondence to: E-mail: lihong.z.chen{at}gsk.com

Abstract

PPAR{gamma} agonists have been shown to have significant therapeutic benefits such as desirable glycemic control in type 2 diabetic patients. However, these agents may cause fluid retention in susceptible individuals. Since PPAR{gamma} is expressed selectively in distal nephron epithelium, we studied the mechanism of PPAR{gamma} agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPAR{gamma} agonist. GI262570 (20mg/kg/day) induced a plasma volume expansion. The plasma volume expansion was accompanied by a small but significant decrease in plasma potassium concentration. Small but significant increases in plasma sodium and chloride concentrations were also observed. These changes in serum electrolytes suggested an activation of the renal mineralocorticoid response system; however, compared to vehicle treated controls, GI262570 treated rats had lower plasma levels of aldosterone. The mRNA levels for a group of genes involved in distal nephron sodium and water absorption are changed in the kidney medulla with GI262570 treatment. In addition, due to a possible rebound effect on epithelial sodium channel (ENaC) activity, a low dose of amiloride did not prevent GI262570 induced fluid retention. On the contrary, the rebound effect after amiloride treatment potentiated GI262570 induced plasma volume expansion. This is at least partially due to a synergistic effect of GI262570 and the rebound from amiloride treatment on ENaC{alpha} expression. In summary, our current data suggest that GI262570 can increase water and sodium reabsorption in distal nephron by stimulating the ENaC and Na,K-ATPase system. This may be an important mechanism for PPAR{gamma} agonist-induced fluid retention.


Key words: PPARgamma, aldosterone, electrolyte, fluid retention, kidney, sodium reabsorption


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