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1Department of Medicine, Division of Endocrinology and Metabolism, and 2Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington, District of Columbia
Submitted 16 December 2005 ; accepted in final form 26 March 2006
Insulin-resistant, obese Zucker rats have blunted pressure natriuresis and are mildly hypertensive. This may involve inappropriate regulation of the renin-angiotensin-aldosterone system. To evaluate mechanisms underlying this defect, we employed the model of aldosterone escape. Male lean (L) and obese (O) Zucker rats were infused with aldosterone (2.8 µg/g body wt3/4) via osmotic minipump while being fed a 0.02% NaCl diet (LS). After 4 days, six rats of each type were switched to a high-NaCl (HS) diet (4%) for 4 additional days. Mean arterial blood pressure measured by radiotelemetry was significantly increased by the HS diet only in obese rats (final mean mmHg): 104 (LLS), 99 (LHS), 103 (OLS), and 115 (OHS). Obese rats had relatively increased renal cortical abundance of the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and whole kidney
- and
-ENaC (epithelial sodium channel) relative to lean rats. However, band density for the thiazide-sensitive (Na-Cl) cotransporter (NCC) was similarly reduced by HS in lean and obese rats (
50%). Obese rats had relatively reduced creatinine clearances and plasma renin activities, effects exacerbated by HS. Furthermore, HS resulted in a 129% increase in urinary nitrates plus nitrites excretion in lean rats and led to, in contrast, a 46% reduction in obese rats. Plasma sodium and potassium concentrations were increased by HS in obese but not lean rats. Thus we demonstrate an impaired response to aldosterone infusion in obese relative to lean Zucker rats. This impairment may involve increased sodium reabsorption via NKCC2 or ENaC, decreased glomerular filtration rate, and/or nitric oxide bioavailability.
kidney; epithelial sodium channel; natriuresis; diuresis; NaPi-2; sodium hydrogen exchanger type 3; Na-K-2Cl cotransporter; BSC1; TSC; NCC; aquaporin; Na-Cl cotransporter; hyperglycemia; proteomics
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