Rosiglitazone Activates Renal Sodium- and Water-Reabsorptive Pathways and Lowers Blood Pressure in Normal Rats

Abstract

Synthetic agonists of the peroxisomal proliferator-activated receptor subtype ␥ (PPAR-␥) are highly beneficial in the treatment of type II diabetes. However, they are also associated with fluid retention and edema, potentially serious side effects of unknown origin. These studies were designed to test the hypothesis that rosiglitazone (RGZ, PPAR-␥ agonist) may activate sodium-and water-reabsorptive processes in the kidney, possibly in response to a drop in mean arterial blood pressure (MAP), as well as directly through PPAR-␥. Targeted proteomics of the major renal sodium and water transporters and channel proteins was used to identify potentially regulated sites of renal sodium and water reabsorption. RGZ (47 or 94 mg/kg diet) was fed to male, Sprague-Dawley rats (ϳ270g) for 3 days. MAP, measured by radiotelemetry, was decreased significantly in rats fed either level of RGZ, relative to control rats. Delta MAP from baseline was Ϫ3.2 Ϯ 1.2 mm Hg in rats fed high-dose RGZ versus ϩ 3.4 Ϯ 0.8 for rats fed control diet. RGZ did not affect feed or water intake, but rats treated with high-dose RGZ had decreased urine volume (by 22%), sodium excretion (44%), kidney weight (9%), and creatinine clearance (35%). RGZ increased whole kidney protein abundance of the ␣-1 subunit of Na-K-ATPase, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), the sodium hydrogen exchanger (NHE3), the aquaporins 2 and 3, and endothelial nitric-oxide synthase. We conclude that both increases in renal tubule transporter abundance and a decrease in glomerular filtration rate likely contribute to the RGZ-induced sodium retention.

Thiazolidinedione-Induced Fluid Retention Is Independent of Collecting Duct αENaC Activity

“…Moreover, rosiglitazone-induced fluid retention and increased body weight was not associated with significant changes in plasma aldosterone or renal expression of the ENaC subunits ␣, ␤, and ␥, confirming previous reports. 15,18 Finally, treatment with rosiglitazone or pioglitazone did not significantly alter ENaC activity when directly assessed by patch-clamp analysis in split-open CDs of C57BL/6 mice.…”

“…18 Similarly, rosiglitazone was reported to increase whole-kidney protein abundance of the ␣ subunit of Na-K-ATPase as well as AQP2, whereas ENaC subunits were not affected; in addition, rosiglitazone increased the expression of the Na ϩ -H ϩ exchanger NHE3, the Na-K-2Cl co-transporter NKCC2, and AQP3. 15 These data indicate that activation of renal Na ϩ reabsorption pathways other than ENaC and of water reabsorption through water channels may also contribute to TZD-induced Na ϩ and fluid retention. Considering the diversity of results, an editorial concluded that the molecular mechanisms and the renal sites of action involved in TZD-induced fluid retention, including a role for ENaC in the CD, have not been clearly established.…”

“…11,12 Lower BP could reduce renal perfusion pressure, thereby increasing renal reabsorption of Na ϩ and fluid. [13][14][15] Conversely, two articles reported that, in mice, genetic knockdown of PPAR-␥ in collecting ducts (CDs) abrogated the ability of the TZDs pioglitazone and rosiglitazone to increase plasma volume and cause weight gain. 16,17 Moreover, TZD-induced weight gain was blocked by amiloride, 17 which is an inhibitor of the epithelial sodium channel (ENaC).…”

Effects of Pioglitazone Versus Glipizide on Body Fat Distribution, Body Water Content, and Hemodynamics in Type 2 Diabetes

“…However, in addition to improved glycemic control, these agents cause weight gain, edema, and redistribution of body fat in individuals with type 2 diabetes (4 -6). Scarce animal and human data have suggested that renal sodium retention could be a causal factor for the development of fluid retention (7,8). Vascular endothelial growth factor (VEGF) also has been implicated as a causal factor in thiazolidinedione-induced edema (9).…”

Effects of Ramipril and Rosiglitazone on Cardiovascular and Renal Outcomes in People With Impaired Glucose Tolerance or Impaired Fasting Glucose

“…Such an effect has been repeatedly noted in other thiazolidinedione studies (12)(13)(14)(15)(16) and appears to be due to sodium and water retention at the renal collecting duct noted above, an increased plasma renin activity (17)(18)(19) perhaps related in part to a modest fall in blood pressure (20,21), and increased insulin action (20). Two echocardiographic studies (22,23) showed that rosiglitazone did not significantly reduce left systolic ventricular function.…”