Chronic candesartan alters expression and activity of NKCC2, NCC, and ENaC in the obese Zucker rat.
The obese Zucker rat reportedly has increased activity of the intrarenal renin-angiotensin-aldosterone system, which conceptually could contribute to elevated salt sensitivity and blood pressure (BP). Our aim was to determine whether there was increased angiotensin II type 1 receptor (AT(1)R)-mediated upregulation of expression or activity of the bumetanide-sensitive Na-K-2Cl cotransporter, the thiazide-sensitive Na-Cl cotransporter (NCC), and/or the epithelial sodium channel (ENaC) in obese vs. lean Zucker rats. Male obese and lean Zucker rats (10-wk old) were fed either 1) control chow (1% NaCl) or 2) chow with candesartan (CAN), an AT(1)R antagonist (25 mg/kg.diet) for 14 wk (n = 8/treatment/body type). BP measured by radiotelemetry, was markedly reduced by CAN ( approximately 20-25 mmHg) in both lean and obese rats with no body-type differences. Obese rats had significantly greater net natriuretic response to single injections of hydrochlorothiazide and benzamil, suggesting increased activity of NCC and ENaC, respectively; however, only the response to benzamil was reduced by CAN. CAN led to a significant reduction in whole kidney levels of NCC and gamma-ENaC (70-kDa band) in both lean and obese rats. However, it significantly increased alpha-ENaC and Na-K-2Cl cotransporter levels, and these increases were greater in obese rats. These studies suggest that relatively increased ENaC, but not NCC activity, in obese rats is due to enhanced AT(1)R activity. CAN attenuated the reduction of several renal transporters in the obese rat kidney. Finally, differences in intrarenal AT(1)R activity do not seem directly responsible for BP differences between lean and obese rats.
Madala Halagappa
Veerendra K
VK
Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington, District of Columbia 20007, USA.
Tiwari
Swasti
S
Riazi
Shahla
S
Hu
Xinqun
X
Ecelbarger
Carolyn M
CM
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004232:Diuretics / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000096:biosynthesis*; D005665:Furosemide / Q000494:pharmacology; D006984:Hypertrophy / Q000188:drug therapy / Q000209:etiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D011955:Receptors, Drug / Q000096:biosynthesis*; D012083:Renin / Q000097:blood; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000235:genetics; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000096:biosynthesis / Q000235:genetics; D028021:Sodium-Potassium-Chloride Symporters / Q000096:biosynthesis*; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000096:biosynthesis*; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004232:Diuretics; D053503:Epithelial Sodium Channels; D044140:Receptor, Angiotensin, Type 1; D011955:Receptors, Drug; C578716:Slc12a1 protein, rat; C578876:Slc12a3 protein, rat; C493559:Slc34a2 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D013777:Tetrazoles; C013407:benzamil; D000804:Angiotensin II; D000584:Amiloride; D005665:Furosemide; D012083:Renin; C081643:candesartan