Renal and vascular mechanisms of thiazolidinedione-induced fluid retention

Abstract

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor subtype gamma (PPARgamma) activators that are clinically used as an insulin sensitizer for glycemic control in patients with type 2 diabetes. Additionally, TZDs exhibit novel anti-inflammatory, antioxidant, and antiproliferative properties, indicating therapeutic potential for a wide variety of diseases associated with diabetes and other conditions. The clinical applications of TZDs are limited by the common major side effect of fluid retention. A better understanding of the molecular mechanism of TZD-induced fluid retention is essential for the development of novel therapies with improved safety profiles. An important breakthrough in the field is the finding that the renal collecting duct is a major site for increased fluid reabsorption in response to rosiglitazone or pioglitazone. New evidence also indicates that increased vascular permeability in adipose tissues may contribute to edema formation and body weight gain. Future research should therefore be directed at achieving a better understanding of the detailed mechanisms of TZD-induced increases in renal sodium transport and in vascular permeability.

Figure 1

Body weight gains in untreated and rosiglitazone (RGZ)-treated PPARγ ^f/f mice (a) and CD PPARγ knockout mice (b) (adapted from [28]).*, P < .05 versus vehicle at the corresponding time point.

Figure 2

Changes in plasma volume in PPARγ ^f/f and CD PPARγ knockout mice following rosiglitazone (RGZ) treatment (adapted from [28]). (a) Hematocrit (Hct) in PPARγ ^f/f and CD PPARγ knockout mice before and after RGZ treatment. (b) Plasma aldosterone levels in PPARγ ^f/f and CD PPARγ knockout mice following RGZ treatment. (c) Determination of plasma volume in PPARγ ^f/f and CD PPARγ KO mice by the Evans blue (EB) dye technique.

Figure 3

The mechanism for thiazolidinedione- (TZD-) induced edema. In the renal collecting duct, PPARγ activation increases sodium reabsorption through ENaC-dependent and independent mechanisms. In the blood vessels of adipose tissues, PPARγ ligands activate PKCß, VEGF, and NO, which together lead to increased endothelial permeability. The increased renal sodium retention at the level of the collecting duct in conjunction with increased vascular permeability may determine edema development.