Abstract

The renin-angiotensin system (RAS) plays a critical role in regulating blood pressure and sodium balance and these actions are mediated through angiotensin type I (AT1) receptors. In the kidney, the RAS acts through three distinct pathways that may influence sodium handling: (1) hemodynamic effects at the level of the glomerular circulation mediated by ATl receptors on renal vasculature (2) direct effects on sodium transport modulated by ATl receptors expressed on proximal tubular epithelial cells (3) regulation of sodium reabsorption in the distal nephron by aldosterone under the control of ATl receptors in the adrenal cortex. In the mouse, two separate ATl receptor genes control these functions: AgtrlA and AgtrlB. Using mouse models in which expression of these ATl receptor genes has been specifically altered using gene targeting, it is proposed to determine the role of ATl angiotensin receptor genes in regulating blood pressure through the following specific aims:
Specific Aim I : To define the role of the ATlA receptor in renal adaptation to altered dietary sodium intake, the hypothesis that abnormal renal sodium handling contributes to sodium dependent blood pressure changes in the AgtrlA (-/-) mice will be studied.
Specific Aim II : To examine the role of renal AgtrlA expression in the regulation of blood pressure, the contribution of renal ATlA receptors to the control of blood pressure in renal cross transplantation experiments between AgtrlA (+/+) and AgtrlA (-/-) mice will be determined.
Specific Aim III : To determine the contribution of renal epithelial actions of angiotensin II to blood pressure and sodium homeostasis transgenic mice that express the ATlA receptor in the kidney only on epithelial cells in the proximal tubule will be developed.
Specific Aim I V: To determine the role of AT1B receptors in blood pressure regulation in AgtrlA (-/-) mice, RAS regulation by dietary sodium, and blood pressure responses will be studied when AT1B receptors are inhibited or absent.
Specific Aim V : To define the contribution of the AgtrlB gene to blood pressure regulation, mice with targeted disruption of the AgtrlB gene will be studied.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL056122-01A1
Application #
2029871
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1997-01-01
Project End
1999-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Chen, Daian; Stegbauer, Johannes; Sparks, Matthew A et al. (2016) Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension. Hypertension 67:1291-7
Chen, Daian; Coffman, Thomas M (2015) AT1 Angiotensin receptors-vascular and renal epithelial pathways for blood pressure regulation. Curr Opin Pharmacol 21:122-6
Sparks, Matthew A; Stegbauer, Johannes; Chen, Daian et al. (2015) Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion. J Am Soc Nephrol 26:2953-62
Xie, Luke; Sparks, Matthew A; Li, Wei et al. (2013) Quantitative susceptibility mapping of kidney inflammation and fibrosis in type 1 angiotensin receptor-deficient mice. NMR Biomed 26:1853-63
Dolber, Paul C; Jin, Huixia; Nassar, Rashid et al. (2013) The effects of Ins2(Akita) diabetes and chronic angiotensin II infusion on cystometric properties in mice. Neurourol Urodyn :
Herrera, Marcela; Sparks, Matthew A; Alfonso-Pecchio, Adolfo R et al. (2013) Lack of specificity of commercial antibodies leads to misidentification of angiotensin type 1 receptor protein. Hypertension 61:253-8
Herrera, Marcela; Coffman, Thomas M (2012) The kidney and hypertension: novel insights from transgenic models. Curr Opin Nephrol Hypertens 21:171-8
Sparks, Matthew A; Parsons, Kelly K; Stegbauer, Johannes et al. (2011) Angiotensin II type 1A receptors in vascular smooth muscle cells do not influence aortic remodeling in hypertension. Hypertension 57:577-85
Stegbauer, Johannes; Gurley, Susan B; Sparks, Matthew A et al. (2011) AT1 receptors in the collecting duct directly modulate the concentration of urine. J Am Soc Nephrol 22:2237-46
Stegbauer, Johannes; Coffman, Thomas M (2011) New insights into angiotensin receptor actions: from blood pressure to aging. Curr Opin Nephrol Hypertens 20:84-8

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