Hypertension is the major risk factor for cardiovascular diseases and affects over 70 million Americans. The kidney sets the long-term level of blood pressure by regulation of body fluid volume and ultimately peripheral resistance. Novel strategies to redirect the inappropriate increases in renal vascular resistance and tubular reabsorption address the problem of sustained hypertension. Adenosine is a major regulator of renal control of fluid balance and renal vascular resistance, acting on specific receptors in the proximal tubule and in the afferent arteriole. These two sites of action provide novel and sensitive regulation of fluid balance and have been targeted to manage fluid volume. Adenosine, type 1 and type 2 receptors (A1-AR, A2- AR) have opposing actions in both tissues. Activation of A1-AR constricts the afferent arteriole and promotes Na+ uptake in the proximal tubule. Activation of A2-AR dilates the afferent arteriole and inhibits Na+ uptake in the proximal tubule. Therefore the balance of these actions plays an important role in renal function, but is currently poorly understood. This project will explore the precise roles of each receptor in the uptake of proximal tubule Na+ and fluid and on the setting of renal vascular resistance mediated by tubuloglomerular feedback during two distinct models of hypertension in A1-AR deficient mice.
Specific Aim one will test the hypothesis that adenosine-1 receptors in the proximal tubule promote Na+ and volume retention during salt- sensitive hypertension and that adenosine-2 receptors modulate that influence. Proximal tubule reabsorption will be measured by renal microperfusion and recollection techniques and correlated to blood pressure.
Specific Aim two will test the hypothesis that adenosine-1 receptors in the afferent arteriole and in the proximal tubule enhances blood pressure increase during angiotensin II-induced hypertension. The role of adenosine-2 receptors as modulators of these effects will also be tested. Proximal tubule reabsorption and tubuloglomerular feedback, measured by renal micropuncture techniques, will be assessed during the early and late stages of hypertension after chronic angiotensin II infusion. In addition, vascular reactivity of afferent arterioles will be contrasted between these two models. Results from these studies will advance our knowledge of adenosine control of renal-dependent blood pressure regulation and identify new targets for therapy.

Public Health Relevance

Hypertension is the leading cause of cardiovascular disease, affecting over 70 million Americans. Novel treatments for the prevention of the development of hypertension would have great benefits. This study will explore an under-appreciated system in the kidney that regulates fluid and salt balance, and try to link it to blood pressure control. The designed experiments will provide new information about the pro-hypertensive role of adenosine receptors, which has been previously unrecognized. This study may lead to the development of novel agents to treat specific forms of hypertension.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Ketchum, Christian J
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Georgetown University
Internal Medicine/Medicine
Schools of Medicine
United States
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Bell, Tracy; Araujo, Magali; Luo, Zaiming et al. (2018) Regulation of fluid reabsorption in rat or mouse proximal renal tubules by asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase 1. Am J Physiol Renal Physiol 315:F74-F78
Welch, W J (2015) Adenosine, type 1 receptors: role in proximal tubule Na+ reabsorption. Acta Physiol (Oxf) 213:242-8
Lai, En Yin; Luo, Zaiming; Onozato, Maristela L et al. (2012) Effects of the antioxidant drug tempol on renal oxygenation in mice with reduced renal mass. Am J Physiol Renal Physiol 303:F64-74
Lee, Dexter L; Bell, Tracy D; Bhupatkar, Jenny et al. (2012) Adenosine A1-receptor knockout mice have a decreased blood pressure response to low-dose ANG II infusion. Am J Physiol Regul Integr Comp Physiol 303:R683-8
Carlström, Mattias; Wilcox, Christopher S; Welch, William J (2011) Adenosine A2A receptor activation attenuates tubuloglomerular feedback responses by stimulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 300:F457-64
Bell, Tracy D; Luo, Zaiming; Welch, William J (2010) Glomerular tubular balance is suppressed in adenosine type 1 receptor-deficient mice. Am J Physiol Renal Physiol 299:F1158-63
Carlström, Mattias; Wilcox, Christopher S; Welch, William J (2010) Adenosine A(2) receptors modulate tubuloglomerular feedback. Am J Physiol Renal Physiol 299:F412-7
Luo, Zaiming; Teerlink, Tom; Griendling, Kathy et al. (2010) Angiotensin II and NADPH oxidase increase ADMA in vascular smooth muscle cells. Hypertension 56:498-504
Palm, Fredrik; Onozato, Maristela; Welch, William J et al. (2010) Blood pressure, blood flow, and oxygenation in the clipped kidney of chronic 2-kidney, 1-clip rats: effects of tempol and Angiotensin blockade. Hypertension 55:298-304
Panico, Carolina; Luo, Zaiming; Damiano, Sara et al. (2009) Renal proximal tubular reabsorption is reduced in adult spontaneously hypertensive rats: roles of superoxide and Na+/H+ exchanger 3. Hypertension 54:1291-7

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