Thiazolidinedione-Induced Fluid Retention: Recent Insights into the Molecular Mechanisms

Hindawi Publishing Corporation PPAR Research Volume 2013, Article ID 628628, 8 pages http://dx.doi.org/10.1155/2013/628628 Review Article Thiazolidinedione-Induced Fluid Retention: Recent Insights into the Molecular Mechanisms Jerzy BeBtowski, Jolanta RachaNczyk, and MirosBaw WBodarczyk Department of Pathophysiology, Medical University of Lublin, 8 Jaczewskiego, 20090 Lublin, Poland Correspondence should be addressed to Jerzy Bełtowski; Received 12 December 2012; Accepted 19 February 2013 Academic Editor: Tianxin Yang Copyright © 2013 Jerzy Bełtowski et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Peroxisome proliferator-activated receptor-𝛾 (PPAR𝛾) 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 PPAR𝛾 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 PPAR𝛾-induced nongenomic transactivation of the epidermal growth factor receptor and downstream extracellular signal-regulated kinases (ERK). 1. Introduction Thiazolidinediones (TZD) are synthetic exogenous agonists of peroxisome proliferator-activated receptor-𝛾 (PPAR𝛾) and are used in the treatment of type 2 diabetes mellitus (T2DM). Currently, two TZDs, rosiglitazone (RGZ) and pioglitazone (PGZ), are available, although rosiglitazone is being withdrawn from the market in Europe and its use is restricted in the USA due to concerns about the increase in prevalence of myocardial infarction in RGZ-treated patients demonstrated in several clinical trials. TZDs increase insulin sensitivity, reduce blood glucose and hemoglobin A1c levels, inhibit adipose tissue lipolysis, and favorably affect adipose tissue hormones (adipokines), decrease microalbuminuria, inhibit inflammation, reduce blood pressure, and counteract hepatic steatosis and fibrosis in experimental animals and in TZDtreated patients [1–3]. However, these medications are not devoid of adverse effects among which fluid retention and edema are among the most important [4, 5]. Thiazolidinediones induce peripheral edema in 5–10% of patients if used in monotherapy and in 15–20% of those cotreated with insulin. Edema results from fluid retention manifested as the increase in body weight and total body water, small but significant 6-7% increase in plasma volume, and reduction of hematocrit, hemoglobin, and serum albumin concentrations. The prevalence and severity of edema are similar in RGZand PGZ-treated patients. TZD-induced edema is usually peripheral. However, these medications may precipitate or aggravate congestive heart failure which is a common comorbidity in diabetic patients, and pulmonary edema in TZDtreated patients has also been occasionally reported. TZDinduced fluid retention is often resistant to diuretics and is relieved only by drug withdrawal. The mechanisms and consequences of TZD-induced fluid retention have been described in several previous articles [6–14]. In this paper, we will focus on recent findings about the effects of TZDs on 2 sodium handling in the kidney. These findings indicate that the mechanism of TZD-induced fluid retention is much more complex and controversial than initially appreciated. 2. Renal Sodium Handling: An Overview Although vascular effects, that is, vasodilation and increase in transendothelial permeability, may contribute to thiazolidinedione-induced edema and fluid retention, there is little doubt that alterations of renal Na+ handling by the kidney play a key role. In the kidney, Na+ is first filtered in glomeruli and then >99% of it is reabsorbed in renal tubules. Sodium reabsorption occurs throughout the nephron with 60–70% of filtered Na+ being reabsorbed in the proximal tubule (PT), 20–25% in the medullary thick ascending limb of Henle’s loop (mTAL), 5–10% in distal convoluted tubule (DCT), and the rest in the collecting duct (CD). Sodium reabsorption consists of two steps. First, Na+ enters the tubular cell through the apical (luminal) membrane carriers which vary along the nephron. In the proximal tubule Na+ reabsorption is accounted for by Na+ /H+ exchanger-3 (NHE3), Na+ -phosphate cotransporter-2 (Na-Pi2), Na+ glucose, and Na+ -amino acid cotransporters. In the mTAL, DCT, and CD apical sodium reabsorption is driven by loop diuretics-sensitive Na+ -K+ -2Cl− cotransporter (NKCC), thiazide-sensitive Na+ -Cl− cotransporter (NCC), and amiloride-sensitive epithelial sodium channel (ENaC), respectively, although these carriers overlap to some extent at transition from one segment to the other. In contrast, the second, active step of Na+ transport, that is, its extrusion from tubular cell to the peritubular space, is always driven by sodium-potassium adenosine triphosphatase (Na+ ,K+ ATPase) irrespectively of the nephron segment. Although even very minor changes in glomerular filtration rate (GFR) may have profound effects on overall Na+ excretion, it is generally assumed that regulation of sodium balance is mainly regulated at the level of tubular reabsorption. The latter process is regulated by a myriad of neurohormonal factors which either stimulate reabsorption and decrease natriuresis, such as norepinephrine, angiotensin II, aldosterone, glucocorticoids, and insulin, or have the opposite effects such as nitric oxide (NO), angiotensin (17), prostaglandins, bradykinin, dopamine, and cardiac natriuretic peptides. Any compound administered systemically may affect renal Na+ handling either directly, by modulating tone of afferent and efferent vessels (and thus affecting GFR) or tubular function, or, indirectly, by modulating these neurohormonal systems. In contrast, if effect of a given compound on isolated tubule segments or tubular cells is examined, only direct mechanisms will be o (...truncated)