In hypertension the pressure natriuresis set point is shifted to a higher pressure, due to an increase in both renal vascular resistance and Na+ reabsorption. The afferent arterioles (Af-Art) and efferent arterioles account for most renal vascular resistance;they control glomerular filtration rate (GFR) and peritubular pressure, and consequently renal function. Af-Art resistance is regulated by factors similar to those that control other arterioles;in addition, the Af-Art is also controlled by tubuloglomerular feedback (TGF). TGF operates via the macula densa, which senses increases in NaCl and sends a signal that constricts the Af-Art. We have evidence that increasing NaCl delivery to the connecting tubule (CNT) dilates the Af-Art, and that this dilatation can be blocked by inhibitors of Na+ transport. We refer to the cross-talk between the CNT and Af-Art as connecting tubule glomerular feedback (CTGF). Here we propose to study CTGF both in vitro and in vivo to determine its physiological role and the mechanisms by which Na+ causes CTGF. We will also study the regulation of CTGF by nitric oxide (NO) and the tubular renin-angiotensin system (RAS), since both NO synthase and renin and angiotensinogen are expressed in the nephron. In vitro and in vivo we propose to test the general hypothesis that Na+ reabsorption by the connecting tubule induces the release of arachidonic acid metabolites that diffuse to and promote dilatation of the Af-Art (CTGF response). Thus CTGF antagonizes vasoconstrictor stimuli such as TGF. The tubular RAS potentiates CTGF by stimulating Na+ transport by the CNT, while NO blunts CTGF by inhibiting this process. We will test this general hypothesis in four Aims.
Aim I will test whether an increase in Na+ reabsorption in the CNT causes an increase in intracellular Ca++ via the Na+/ Ca++ exchanger, which results in Ca++-mediated activation of phospholipases, release of arachidonic acid, and formation of eicosanoids which diffuse to the Af-Art and cause dilatation.
Aim II will test whether in vivo, CTGF opposes the vasoconstrictor effect of TGF and whether in the absence of TGF, CTGF causes Af-Art dilatation.
Aim III will test whether NO produced by NOS 3 in the CNT decreases CTGF by blocking Na+ transport by ENaC via activation of guanylyl cyclase, increasing cGMP, activating cGMP-dependent protein kinase, and reducing cAMP.
Aim I V will test whether the tubular RAS via Ang II and the AT1 receptor enhances CTGF directly by acting on ENaC and indirectly by stimulating the release of O2- via NADPH oxidase. This will be the first study to determine the role of the renal connecting tubule in the regulation of afferent arteriole resistance and glomerular filtration rate. This is a novel mechanism that will provide new insights on the regulation of renal function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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OH, Youngsuk
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Henry Ford Health System
United States
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Ren, Yilin; D'Ambrosio, Martin A; Wang, Hong et al. (2012) Mechanisms of angiotensin II-enhanced connecting tubule glomerular feedback. Am J Physiol Renal Physiol 303:F259-65
Wang, Hong; D'Ambrosio, Martin A; Garvin, Jeffrey L et al. (2012) Connecting tubule glomerular feedback mediates acute tubuloglomerular feedback resetting. Am J Physiol Renal Physiol 302:F1300-4
Wang, Hong; Garvin, Jeffrey L; D'Ambrosio, Martin A et al. (2011) Heme oxygenase metabolites inhibit tubuloglomerular feedback in vivo. Am J Physiol Heart Circ Physiol 300:H1320-6
Wang, H; Garvin, J L; D'Ambrosio, M A et al. (2010) Connecting tubule glomerular feedback antagonizes tubuloglomerular feedback in vivo. Am J Physiol Renal Physiol 299:F1374-8