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PPAR Agonists, Modulation of Ion Transporters, and Fluid Retention

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PPAR Agonists, Modulation of Ion Transporters, and Fluid Retention EDITORIALS www.jasn.org UP FRONT MATTERS PPAR␥ Agonists, Modulation lation of salt reabsorption and, consequently, BP. It is logical, therefore, to postulate that ENaC is a likely target of Ion Transporters, and Fluid of a PPAR␥ agonist effect. Unfortunately, studies per- formed to substantiate this relationship are contradictory, Retention and it is difficult to establish a consensus as to potential † mechanisms. Charity Nofziger* and Bonnie L. Blazer-Yost Two different collecting-duct-specific PPAR␥ null mouse *Paracelsus Medical University, Institute of Pharmacology and ␥ Toxicology, Salzburg, Austria; and †Department of Biology, Indi- models showed significant reductions in PPAR -agonist-in- ana University–Purdue University Indianapolis, Indianapolis, duced weight gain and plasma volume expansion compared Indiana with those of wild-type littermates,6,7 substantiating the no- J Am Soc Nephrol 20: 2481–2483, 2009. tion that the collecting duct plays a primary role in the devel- doi: 10.1681/ASN.2009060673 opment of PPAR␥-induced volume expansion. Primary cell cultures derived from the collecting duct of wild-type, but ␥ ␥ ␥ not from collecting-duct-specific PPAR null mice, show in- Peroxisome proliferator-activated receptor (PPAR ) ago- creased amiloride-sensitive 22Naϩ flux in response to PPAR␥ nists, also known as thiazolidinediones (TZDs), are used as agonist challenge.6,7 In contrast, in separate studies, neither insulin-sensitizing agents to treat type 2 diabetes. Examples pioglitazone nor rosiglitazone increased ENaC activity in include pioglitazone (Actos®), rosiglitazone (Avandia®), and three well-characterized culture models of principal cells as others such as troglitazone, farglitazar (GI262570), and measured by short-circuit current electrophysiology.8 Inter- GW7845. Side effects of TZD therapy include fluid retention estingly, 24-h treatment with either GI262570 or pioglitazone and peripheral edema. The weight gain from fluid retention is decreased vasopressin-stimulated, amiloride-sensitive cur- undesirable from a cosmetic standpoint but more seriously rent in Madin–Darby canine kidney clone 7 (MDCK-C7) 1 can adversely affect comorbidity in the diabetic state. 9 ␥ cells. Reported effects of PPAR agonists on cardiovascular Biochemical investigations demonstrate agonist-mediated function are mixed. One recent high-profile study found that changes in ENaC subunit mRNA or protein abundance or in rosiglitazone increases the risk of death from cardiovascular proteins known to regulate ENaC with little consensus across 2 although other studies observe beneficial effects of disease, studies. Several groups found no change in ENaC subunit pioglitazone on major cardiovascular events in humans3 and mRNA concentrations in rodents treated with PPAR␥ agonists, protection against ischemia–reperfusion injury and reduc- whereas other studies found increases in ENaC␣, decreases in tion of myocardial infarct size in animal models.4 Regardless ␤ ␥ ␥ ENaC , and either increases or decreases in ENaC . Serum glu- of the risk–benefit relationships of PPAR agonist therapy, it cocorticoid-induced kinase, an intracellular mediator that reg- is clear that fluid retention exacerbates compromised cardiac ulates ENaC expression, increases upon exposure to PPAR␥ function and lessens patient compliance with drug treatment. ␥ agonists in some studies but not in others. Unfortunately, PPAR -agonist-induced fluid retention is re- In vivo studies using ENaC inhibitors have been unable to fractory to most first-line diuretic therapies.5 ␥ ␥ clarify the question of the importance of the ENaC in PPAR - The nature of PPAR -agonist-induced fluid retention mediated fluid retention. The data regarding the efficacy of suggests an integrated physiologic response that includes a amiloride, a selective ENaC blocker, in alleviating fluid reten- primary effect on renal regulation of salt and water bal- 10 ␥ tion are contradictory, with one study showing no effect ance. PPAR is expressed in the collecting duct, suggesting and another showing complete reversal of water-induced that ligands for this receptor modulate salt and water ho- weight gain.7 meostasis through ion transport systems in this nephron ϩ To more definitively address the involvement of ENaC, segment. The epithelial Na channel (ENaC) expressed in Vallon et al. used a mouse model containing a collecting- collecting duct principal cells is regulated by steroid (aldo- duct-specific gene inactivation of ENaC␣. In these mice, sterone) and peptide hormones (insulin, IGF-1, and vaso- functional inactivation of ENaC did not protect animals pressin) and represents a key control point for the modu- against rosiglitazone-induced weight gain, fluid retention, or decreased hematocrit.11 These data argue against a primary Published online ahead of print. Publication date available at www.jasn.org. role for ENaC in agonist-mediated fluid retention. Taken together, the composite data are consistent with the Correspondence: Dr. Bonnie L. Blazer-Yost, Department of Biology, Indiana University–Purdue University Indianapolis, Indianapolis, IN 46202. Phone: collecting duct as the site at which PPAR␥ agonists act to (317) 278-1145; Fax: (317) 274-2846; E-mail: [email protected] induce fluid retention. The data do not, however, make a Copyright ᮊ 2009 by the American Society of Nephrology strong case for ENaC as the primary target of the agonists. In J Am Soc Nephrol 20: 2481–2489, 2009 ISSN : 1046-6673/2012-2481 2481 EDITORIALS www.jasn.org light of what is currently understood about renal physiology transactivation profiles.9 The PPAR␥-agonist-induced de- and the role of ENaC in BP and volume regulation, several crease in anion secretion is the result of decreases in levels of anomalies in physiologic principles also argue against stimula- mRNA encoding CFTR (cystic fibrosis transmembrane regu- tion of ENaC as the initial target of PPAR␥-agonist-mediated lator). There are numerous reports describing changes in renal fluid retention. and plasma Naϩ and Kϩ concentrations in response to treat- Clinical data show that stimulation of ENaC activity leads to ment with PPAR␥ agonist. Remarkably, one study shows a an increase in Naϩ and water reabsorption, resulting in an statistically detectable increase in plasma ClϪ concentration increase in BP. Human gain-of-function mutations in ENaC after a 4-d challenge with GI262570.10 These data are consis- (Liddle’s syndrome) cause severe hypertension early in life. As tent with those describing decreased secretion of the anion in mentioned previously, aldosterone and insulin also increase response to PPAR␥ agonists in continuous cell lines. ENaC-mediated Naϩ absorption. Hyperaldosteronism arising The paradigm of PPAR␥-mediated decreases in CFTR expres- from pituitary tumors is not an uncommon cause of hyperten- sion also is validated by studies in intestinal cells. Oral administra- sion. We and others postulate that the hyperinsulinemia seen tion of rosiglitazone to mice for 8 d reduces intestinal forskolin- in prediabetic states contributes to the development of the ac- stimulated anion secretion and substantially inhibits cholera- companying hypertension. In contrast, ENaC inhibitors, such toxin-induced intestinal fluid accumulation.15 In HT29 intestinal as amiloride, or naturally occurring loss-of-function muta- cells,5doftreatment with rosiglitazone inhibits cAMP-depen- tions in the channel lead to salt wasting and a decrease in BP. dent ClϪ secretion concomitantly with a decrease in the protein ϩ ϩ Ϫ A meta-analysis of 37 clinical trials examining correlations expression of CFTR, Na /K /2Cl , and KCNQ1.15 Thus, the between PPAR␥ agonists and BP shows that these drugs lower strongest and most consistent evidence to date suggests that the BP.12 Consistent with these results, human loss-of-function primary effect of PPAR␥ agonists in polarized epithelia is a de- mutations in endogenous PPAR␥ are associated with severe crease in the expression of ClϪ channels. insulin resistance and with early onset hypertension.13 Thus, In summary, a compendium of data suggests that PPAR␥ ago- there is a consensus that PPAR␥ agonists decrease BP and loss nists cause fluid retention through effects on the renal collecting of PPAR␥ increases BP. duct. Because hormonal regulation of ENaC plays a major role in This presents an interesting quandary when evoking ENaC- electrolyte and fluid homeostasis, it is logical to hypothesize that mediated mechanisms to simultaneously explain PPAR␥-ago- this transporter is the target of PPAR␥ action. However, physio- nist-mediated increases in fluid retention and decreases in BP. logic principles argue against a stimulation of ENaC simulta- The correlation between Naϩ reabsorption and BP in PPAR␥- neously with a decrease in BP. We postulate that the initial flux of agonist-treated subjects is the converse of what would be pre- fluid from the vasculature may be driven by the changes in ClϪ dicted if the effects were mediated by increases in ENaC abun- balance. Naϩ and fluid retention would be a compensatory re- dance or activity. Accumulating data raise the possibility that sponse to the loss of fluid from the vasculature and into the inter- changes in Naϩ balance during PPAR␥ agonist therapy may be stitial space. Additional in vivo investigations are needed to fully secondary to other, more immediate responses. substantiate the hypothesis of regulation of ClϪ transport in Although the role of ClϪ in the regulation of body fluid ho- PPAR␥-agonist-induced
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