GI262570, a Peroxisome Proliferator-Activated Receptor γ Agonist, Changes Electrolytes and Water Reabsorption from the Distal Nephron in Rats

Abstract

Peroxisome proliferator-activated receptor-␥ (PPAR␥) 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␥ is expressed selectively in distal nephron epithelium, we studied the mechanism of PPAR␥ agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPAR␥ agonist. GI262570 (20 mg/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, GI262570-treated rats had lower plasma levels of aldosterone compared with vehicle-treated controls. 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␣ expression. In summary, our current data suggest that GI262570 can increase water and sodium reabsorption in distal nephron by stimulating the ENaC and Na,KATPase system. This may be an important mechanism for PPAR␥ agonist-induced fluid retention.

PPARγ Agonists, Modulation of Ion Transporters, and Fluid Retention

“…Remarkably, one study shows a statistically detectable increase in plasma Cl Ϫ concentration after a 4-d challenge with GI262570. 10 These data are consistent with those describing decreased secretion of the anion in response to PPAR␥ agonists in continuous cell lines.…”

“…The data regarding the efficacy of amiloride, a selective ENaC blocker, in alleviating fluid retention are contradictory, with one study showing no effect 10 and another showing complete reversal of water-induced weight gain. 7 To more definitively address the involvement of ENaC, Vallon et al used a mouse model containing a collectingduct-specific gene inactivation of ENaC␣.…”

Thiazolidinedione-Induced Fluid Retention Is Independent of Collecting Duct αENaC Activity

“…Moreover, rosiglitazone-induced fluid retention and increased body weight was not associated with significant changes in plasma aldosterone or renal expression of the ENaC subunits ␣, ␤, and ␥, confirming previous reports. 15,18 Finally, treatment with rosiglitazone or pioglitazone did not significantly alter ENaC activity when directly assessed by patch-clamp analysis in split-open CDs of C57BL/6 mice.…”

“…17 The PPAR-␥ agonist farglitazar also increased blood volume, and this effect was associated with increased renal expression of the ␣ subunit of Na-K-ATPase and aquaporin 2 (AQP2), whereas the renal expression of the ENaC subunits was not significantly altered, and amiloride did not prevent blood volume expansion. 18 Similarly, rosiglitazone was reported to increase whole-kidney protein abundance of the ␣ subunit of Na-K-ATPase as well as AQP2, whereas ENaC subunits were not affected; in addition, rosiglitazone increased the expression of the Na ϩ -H ϩ exchanger NHE3, the Na-K-2Cl co-transporter NKCC2, and AQP3. 15 These data indicate that activation of renal Na ϩ reabsorption pathways other than ENaC and of water reabsorption through water channels may also contribute to TZD-induced Na ϩ and fluid retention.…”

Effect of Various Diuretic Treatments on Rosiglitazone-Induced Fluid Retention

“…TZD seem to have a mild arterial vasodilatory action, which potentially could induce peripheral edema, but a clear connection between vasodilation and volume expansion has not been made. In vitro and animal data suggest that PPAR-␥ agonists stimulate sodium reabsorption in the distal nephron by upregulating the expression and the translocation of the collecting duct epithelial sodium channel (ENaC␣) (17,18). Selective deletion of the gene that encodes PPAR-␥ in the collecting duct results in increased renal sodium excretion and prevents TZDinduced fluid retention, hemodilution, and weight gain in transgenic mice (19).…”