Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lowers blood pressure in normal rats.
Synthetic agonists of the peroxisomal proliferator-activated receptor subtype gamma (PPAR-gamma) 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-gamma 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-gamma. 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 (approximately 270g) 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 -3.2 +/- 1.2 mm Hg in rats fed high-dose RGZ versus + 3.4 +/- 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 alpha-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.
Department of Medicine, Georgetown University, Washington, DC 20057-1412, USA.
Jian
J
Song
Mark A
MA
Knepper
Xinqun
X
Hu
Joseph G
JG
Verbalis
Carolyn A
CA
Ecelbarger
D000818:Animals; D051398:Aquaporin 1; D051400:Aquaporin 3; D020346:Aquaporins / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014867:Water / Q000378:metabolism
C496022:Aqp1 protein, rat; C496029:Aqp3 protein, rat; D020346:Aquaporins; D007004:Hypoglycemic Agents; D015222:Sodium Channels; D045162:Thiazolidinediones; D014867:Water; D000077154:Rosiglitazone; D051398:Aquaporin 1; D051400:Aquaporin 3; D012964:Sodium; C499075:Atp1a1 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase