Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption

Abstract

Thiazolidinediones (TZDs) are widely used to treat type 2 diabetes mellitus; however, their use is complicated by systemic fluid retention. Along the nephron, the pharmacological target of TZDs, peroxisome proliferator-activated receptor-gamma (PPARgamma, encoded by Pparg), is most abundant in the collecting duct. Here we show that mice treated with TZDs experience early weight gain from increased total body water. Weight gain was blocked by the collecting duct-specific diuretic amiloride and was also prevented by deletion of Pparg from the collecting duct, using Pparg (flox/flox) mice. Deletion of collecting duct Pparg decreased renal Na(+) avidity and increased plasma aldosterone. Treating cultured collecting ducts with TZDs increased amiloride-sensitive Na(+) absorption and Scnn1g mRNA (encoding the epithelial Na(+) channel ENaCgamma) expression through a PPARgamma-dependent pathway. These studies identify Scnn1g as a PPARgamma target gene in the collecting duct. Activation of this pathway mediates fluid retention associated with TZDs, and suggests amiloride might provide a specific therapy.

Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals

“…Shortterm animal studies also show that there is a rapid increase in body weight during the first week of treatment, clearly due to an increase in water content [6,7] and an increase in the epithelial sodium channel (ENaC) activity. These effects were inhibited by amiloride, an ENaC inhibitor, and abolished in mice with specific deletion of the collecting duct PPAR-γ suggesting an important role of glitazoneinduced sodium retention through ENaC.…”

“…Both direct and indirect effects of glitazones on renal sodium reabsorption have been proposed, through the direct activation of tubular peroxisome proliferator-activated receptor (PPAR)-γ or indirectly through the activation of compensatory mechanisms secondary to the glitazone-induced vasodilation [6][7][8]. Experimental studies have shown that glitazones may increase sodium transport in the proximal convoluted tubules, the thick ascending limb and the collecting duct [9,10].…”

Fat poetry: a kingdom for PPARγ

“…The latter, which can be explained by PPARg stimulation of ENaC-mediated renal salt absorption [218], might be the cause of an increased incidence of congestive heart failure [219], an outcome also observed in rats where rosiglitazone treatment is associated with increased post-myocardial infarction mortality [220]. However, this issue is still under debate as the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) showed recently that treatment of type 2 diabetic patients with pioglitazone, another TZD drug, improved their cardiovascular outcome [113].…”

“…SPPARgMs would separate the effects of PPARg on lipid and glucose metabolisms as well as on different organ systems (gastrointestinal, immune, cardiovascular). The selective action of such compounds is thought to depend on different structural configurations induced in the ligand-binding domain by their interaction with the receptor, allowing recruitment of different complexes of cofactors that impact on the activation or repression of specific sets of target genes in different tissues [146,218,[226][227][228][229][230][231].…”

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

“…On the one hand, PPARγ agonists were found to upregulate mRNA levels of SCNN1G encoding for the gamma subunit of ENaC in a mouse inner medullary collecting duct cell line [19]. On the other hand PPARγ agonists have been shown to stimulate the transcription of the serum and glucocorticoid-inducible kinase SGK1 [22], which, in turn, was suggested to enhance the surface expression of ENaCα [22].…”