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

Department of Molecular Pharmacology, GlaxoSmithKline, Inc., Five Moore Drive, Research Triangle Park, NC 27709, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 03/2005; 312(2):718-25. DOI: 10.1124/jpet.104.074088
Source: PubMed


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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    • "Because in the kidney NO increases GFR and inhibits tubular Na + reabsorption, these results indicate that downregulation of NO is not involved in antinatriuretic effect of rosiglitazone [17]. The different conclusions from above-mentioned studies, that is, TZDs induce fluid retention by primarily tubular [15] [16] or glomerular [17] mechanisms, may result from using different PPARí µí»¾ agonists (farglitazar versus rosiglitazone) as well as time and dose of agonist administration. In particular, short-term administration of rosiglitazone reduced GFR [17]; the effect which might disappear after prolonged treatment due to increase in extracellular fluid volume as well as systemic adaptive neurohormonal mechanisms. "
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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).
    Full-text · Article · Mar 2013 · PPAR Research
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    • "In addition, TZDs increase the activity of the ENaC and Na-K-ATPase system, independent of the increase in ENaC expression [24, 25]. There are also data to suggest that ENaC-independent mechanisms might be involved, since amiloride, an inhibitor of ENaC, fails to prevent TZD-induced fluid retention [24, 25]. Accordingly, aquaporin-2 has been also implicated in this phenomenon [26]. "
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    ABSTRACT: The incidence of type 2 (T2D) diabetes and other chronic conditions associated with insulin resistance is increasing at an alarming rate, underscoring the need for effective and safe therapeutic strategies. Peroxisome-proliferator-activated receptor gamma (PPARγ) has emerged as a critical regulator of glucose homeostasis, lipid homeostasis, and vascular inflammation. Currently marketed drugs targeting this receptor, the thiazolidinediones (TZDs), have proven benefits on insulin resistance and hyperglycemia associated with T2D. Unfortunately, they have been associated with long-term unfavorable effects on health, such as weight gain, plasma volume expansion, bone loss, cardiovascular toxicity, and possibly cancer, and these safety concerns have led to reduced interest for many PPARγ ligands. However, over the last years, data from human genetic studies, animal models, and studies with ligands have increased our understanding of PPARγ's actions and provided important insights into how ligand development strategies could be optimized to increase effectiveness and safety of PPARγ-based therapies.
    Full-text · Article · Jun 2012 · PPAR Research
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    • "). There is some thought that amiloride or spironolactone could decrease this effect (Chen et al., 2005). Another adverse effect of glitazones related to PPARγ activation is on bone; glitazones decrease bone formation and bone mass, and increase fracture rates, at least in women (Bodmer et al., 2009). "
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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.
    Full-text · Article · Mar 2011 · Frontiers in Pharmacology
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