Obesity and insulin resistance are associated with hypertension. Inappropriate retention of sodium by the kidney is likely to play a major role. We previously showed that the obese Zucker rat (a model for these disorders) have increased renal protein abundance for three major sodium transport proteins: the alpha-1 subunit of Na-K-ATPase, the thiazide-sensitive NaCI cotransporter (NCC or TSC) and the beta-subunit of the epithelial sodium channel (ENaC). In contrast, as, they aged, obese rats developed renal hypertrophy along with diabetes and had a relative decrease in many important salt and water transport proteins, as compared to age-matched controls. We suggest that dysregulation of several important hormone systems in sodium balance may play a role in both alterations in sodium transport protein expression, as well as, the rapid develop of nephropathy. Candidate systems include the renin-angiotensin-aldosterone system (RAAS) and insulin (and or insulin resistance). We hypothesize that dysregulation of major sodium transport proteins of the kidney in the obese Zucker rat with age, is due at least in part to increased RAAS activity, and hyperinsulinemia, which in combination, result in inappropriate sodium retention and elevated blood pressure.
Our specific aims i nclude: 1) to determine if angiotensin II At1a receptor expression, binding, and activity is upregulated in the obese Zucker rat and whether this upregulation plays a role in changes in renal sodium transporter regulation, blood pressure, and renal hypertrophy; 2) to determine if enhanced mineralocorticoid receptor (MR) activity plays a role in increased whole kidney protein abundance of the thiazide-sensitive NaCI cotransporter (NCC), blood pressure, and renal hypertrophy, in the obese Zucker rat; 3) to determine the cellular location and sensitivity of the renal insulin receptor in obese Zucker rats relative to lean age-mates; 4) to determine whether treatment of insulin resistance with a PPAR-gamma agonist will decrease relative renal protein abundance of NCC, beta-ENaC, and Na-K-ATPase, as well as reduce blood pressure and renal hypertrophy in the obese Zucker rat, and whether these effects are reversed with short-term insulin infusion. These studies will allow us to determine the importance of each of these potential regulatory hormone systems in dyregulation of sodium transporter expression, sodium balance, and blood pressure in these obese rats.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073193-03
Application #
6900324
Study Section
Special Emphasis Panel (ZHL1-CSR-S (F1))
Program Officer
Barouch, Winifred
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$310,400
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
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