Rosiglitazone regulates ENaC and Na-K-2Cl cotransporter (NKCC2) abundance in the obese Zucker rat.
OBJECTIVE
Progressive diabetes is associated renal remodeling, which we previously showed correlated to reduced protein abundance of several major renal sodium transporters and channel subunits in the obese Zucker rat. Here we test whether rosiglitazone (RGZ), a peroxisome proliferator-activated subtype gamma receptor agonist, would be protective and attenuate these changes.


METHODS
Male, obese and lean Zucker rats (9 weeks old) were randomly divided (n = 6/group) to receive control diet with or without RGZ at 3 mg/kg.bw/day for 12 weeks.


RESULTS
RGZ normalized blood glucose and plasma fructosamine levels in obese rats. Obese control rats had relatively increased fractional excretion of sodium (FE(Na), sodium excretion relative to creatinine). Nonetheless, both obese and RGZ-treated rats had relatively higher 24-hour net sodium balances. Immunoblotting revealed obese rats had significantly reduced renal cortical protein abundances of the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and the sodium hydrogen exchanger (NHE3). RGZ normalized NKCC2 abundance and increased the abundance of the alpha-subunit of the epithelial sodium channel (ENaC). In contrast, in the outer medulla, obese rats had increased abundance of NKCC2, gamma-ENaC (85-kDa), and endothelial NOS. Furthermore, RGZ caused a decrease in the abundance of cortical beta- and gamma-ENaC (85-kDa). Finally, the whole kidney abundances of alpha-1 Na-K-ATPase, alpha- beta-, and gamma-ENaC (70-kDa band) positively correlated with net sodium balance, whereas NKCC2 was negatively correlated to FE(Na).


CONCLUSIONS
Chronic RGZ treatment of obese Zucker rats may preserve renal sodium reabsorptive capacity by its indirect actions to attenuate hyperglycemia as well as direct effects on transporter abundance and activity.
Riazi
Shahla
S
Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington, DC 20057-1412, USA.
Khan
Osman
O
Tiwari
Swasti
S
Hu
Xinqun
X
Ecelbarger
Carolyn A
CA
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000517:prevention & control*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1; D045162:Thiazolidinediones / Q000008:administration & dosage*; D014018:Tissue Distribution
D053503:Epithelial Sodium Channels; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D045162:Thiazolidinediones; D000077154:Rosiglitazone