Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention

Abstract

The peroxisome proliferator-activated receptor subtype ␥ (PPAR␥) ligands, namely the synthetic insulin-sensitizing thiazolidinedione (TZD) compounds, have demonstrated great potential in the treatment of type II diabetes. However, their clinical applicability is limited by a common and serious side effect of edema. To address the mechanism of TZD-induced edema, we generated mice with collecting duct (CD)-specific disruption of the PPAR␥ gene. We found that mice with CD knockout of this receptor were resistant to the rosiglitazone-(RGZ) induced increases in body weight and plasma volume expansion found in control mice expressing PPAR␥ in the CD. RGZ reduced urinary sodium excretion in control and not in conditional knockout mice. Furthermore, RGZ stimulated sodium transport in primary cultures of CD cells expressing PPAR␥ and not in cells lacking this receptor. These findings demonstrate a PPAR␥-dependent pathway in regulation of sodium transport in the CD that underlies TZD-induced fluid retention.roziglitazone ͉ Cre recombinase ͉ Evans blue technique T hiazolidinediones (TZDs), synthetic insulin-sensitizing drugs that include troglitazone, pioglitazone, and rosiglitazone (RGZ), are highly effective in the treatment of type II diabetes. TZDs are believed to mediate their antidiabetic effect via activation of peroxisome proliferator-activated receptor ␥ (PPAR␥) (1). In addition to lowering blood glucose, these drugs also benefit cardiovascular parameters, such as blood pressure and endothelial function (2, 3). However, fluid retention, presented as rapid weight gain, and peripheral and pulmonary edema have emerged as the most common and serious side effects of TZDs (4-6). Global awareness of this side effect has increased as a result of the growing number of reported cases. In a recent issue of Circulation (7), the American Heart Association and American Diabetes Association jointly issued a Consensus Statement commenting on the safety of TZD as related to edema. The mechanisms of fluid retention in patients treated with TZDs are poorly understood and may involve a number of factors, including reduction of urinary sodium excretion (8), alteration of endothelial permeability (9), increased sympathetic nervous system activity (10), or altered interstitial ion transport (11). To evaluate the relative contributions of these individual mechanisms, tissue-or cell-type-specific approaches are needed in carefully designed studies.PPARs are a group of zinc finger-containing transcription factors, representing a family of the nuclear hormone receptor gene superfamily. To date, three subtypes of PPARs encoded by different genes have been described from several species: PPAR␣, -␤͞␦, and -␥ (12, 13). They share a high degree of similarity in their overall amino acid sequences, particularly in the DNA-binding domain (14). The three isoforms of the PPARs heterodimerize with retinoid X receptor, bind to the same peroxisome proliferatorresponsive element in the promoter regions of their target genes, and modulate gene transcripti...

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].…”

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

“…A high-energy state, such as obesity, is associated with disturbance of electrolytes and fluid balance and hypertension (46,47), whereas a low-energy state, such as fasting, induces natriuresis and diuresis (48,49). Along this line, activation of PPARγ, a key regulator of glucose metabolism and adipogenesis, causes body weight gain and plasma volume expansion (50,51). In the present study, we discovered that LXR against TO901317 exerted a profound diuretic action in mice as suggested by polyuria, polydipsia, hypoosmotic urine, and contraction of plasma volume.…”

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

“…Therefore, the volume retaining effect of PPARγ-agonists may be due to stimulation of the epithelial sodium channel (ENaC) in the distal nephron [26]. Accordingly, gene-targeted mice with a collecting duct-specific deletion of PPARγ are apparently protected against PPARγ agonists-induced fluid retention [51].…”