Hypertension affects more than 60 million people in the US and despite its diverse causes;blockade of the renin-angiotensin system (RAS) lowers blood pressure in the majority of hypertensive patients. The clinical significance of the RAS is exemplified by the substantial benefit of RAS blockade (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) on overall cardiovascular and renal health. We have used gene-targeting in mice to identify the cellular targets of the RAS in the kidney to control blood pressure. Our recent studies have identified the renal proximal tubule as a critical site for RAS to regulate blood pressure in the intact animal. Mice lacking AT1 receptors only from renal proximal tubule had lower blood pressures, associated with protection against angiotensin II-induced hypertension and alterations in urinary sodium handling. We now hypothesize that AT1 receptors in the renal proximal tubule set the level of the intrarenal RAS which can then exert effects in different segments of the nephron to regulate blood pressure and fluid homeostasis. The overall goal of this project is to establish the capacity of angiotensin receptors in the renal proximal tubule to regulate blood pressure, which we propose to accomplish through the following specific aims: To determine how proximal tubule AT1 receptors regulate epithelial function (1) directly within the PT and (2) distally, along the nephron. We will examine specific pathways such as intra- renal RAS, oxidative stress, and transporter regulation related to angiotensin signaling in the renal proximal tubule.

Public Health Relevance

Hypertension affects more than 60 million people in the US and contributes to end-organ damage such as heart failure, stroke and kidney failure. The renin-angiotensin system acts via angiotensin receptors in the kidney to regulate blood pressure by influencing rates of fluid reabsorption. Our application utilizes genetic mouse models and sophisticated analytical techniques to identify mechanisms by which angiotensin receptors in the kidney control blood pressure so that we can more precisely target treatments for hypertension.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Ketchum, Christian J
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Eriguchi, Masahiro; Lin, Mercury; Yamashita, Michifumi et al. (2018) Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy. Am J Physiol Renal Physiol 314:F531-F542
Leete, Jessica; Gurley, Susan; Layton, Anita (2018) Modeling Sex Differences in the Renin Angiotensin System and the Efficacy of Antihypertensive Therapies. Comput Chem Eng 112:253-264
van Haaster, Marloes C; McDonough, Alicia A; Gurley, Susan B (2018) Blood pressure regulation by the angiotensin type 1 receptor in the proximal tubule. Curr Opin Nephrol Hypertens 27:1-7
Giani, Jorge F; Eriguchi, Masahiro; Bernstein, Ellen A et al. (2017) Renal tubular angiotensin converting enzyme isĀ responsible for nitro-L-arginine methyl esterĀ (L-NAME)-induced salt sensitivity. Kidney Int 91:856-867
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