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+- 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 Currently, two TZDs, rosiglitazone (RGZ) and pioglitazone (PGZ), are available, although rosiglitazone is being withdrawn from the market in Europe and its use is restricted in the USA due to concerns about the increase in prevalence of myocardial infarction in RGZ-treated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 TZD-treated 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
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