GI262570, a Peroxisome Proliferator-Activated Receptor γ Agonist, Changes Electrolytes and Water Reabsorption from the Distal Nephron in Rats
ABSTRACT Peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma is expressed selectively in distal nephron epithelium, we studied the mechanism of PPARgamma agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPARgamma 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 ENaCalpha 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 PPARgamma agonist-induced fluid retention.
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ABSTRACT: Peroxisome proliferator-activated receptor- γ (PPAR γ ) agonists such as rosiglitazone and pioglitazone are used to improve insulin sensitivity in patients with diabetes mellitus. However, thiazolidinediones induce fluid retention, edema, and sometimes precipitate or exacerbate heart failure in a subset of patients. The mechanism through which thiazolidinediones induce fluid retention is controversial. Most studies suggest that this effect results from the increase in tubular sodium and water reabsorption in the kidney, but the role of specific nephron segments and sodium carriers involved is less clear. Some studies suggested that PPAR γ agonist stimulates Na(+) reabsorption in the collecting duct by activating epithelial Na(+) channel (ENaC), either directly or through serum and glucocorticoid-regulated kinase-1 (SGK-1). However, other studies did not confirm this mechanism and even report the suppression of ENaC. Alternative mechanisms in the collecting duct include stimulation of non-ENaC sodium channel or inhibition of chloride secretion to the tubular lumen. In addition, thiazolidinediones may augment sodium reabsorption in the proximal tubule by stimulating the expression and activity of apical Na(+)/H(+) exchanger-3 and basolateral Na(+)-HCO3 (-) cotransporter as well as of Na(+),K(+)-ATPase. These effects are mediated by PPAR γ -induced nongenomic transactivation of the epidermal growth factor receptor and downstream extracellular signal-regulated kinases (ERK).PPAR Research 03/2013; 2013:628628. DOI:10.1155/2013/628628
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ABSTRACT: Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor γ (PPARγ) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARγ-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARγ-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.Frontiers in Pharmacology 03/2011; 2:14. DOI:10.3389/fphar.2011.00014
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ABSTRACT: Involvement of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) in kidney physiology has been explored recently. Synthetic PPARgamma ligands can ameliorate the diabetic kidney disease through different mechanisms, involving inhibition of mesangial cell growth, reduction of mesangial matrix, and cytokine production of glomerular cells as well as promoting endothelial cell survival within the kidney glomeruli. Activation of PPARgamma has additional profibrotic consequences, which can contribute to wound healing in diabetic glomerulonephritis. Beside many beneficial effects, PPARgamma activation, however, can lead to severe water retention, a common side effect of thiazolidinedione therapy. This unwanted effect is due to the activation of PPARgamma in the mesonephric distal collecting system, where PPARgamma positively regulates sodium and water resorbtion leading to the expansion of interstitial fluid volume. Recent studies indicate that PPARgamma is also involved in the normal kidney development, renal lipid metabolism, and activation of the renin-angiotensin system. In this paper, we give a synopsis of the current knowledge on PPARgamma functions in kidney phyisology and pathophysiology.PPAR Research 02/2008; 2008:183108. DOI:10.1155/2008/183108