Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Department of Medicine, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, NC 27710, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2006; 103(47):17985-90. DOI: 10.1073/pnas.0605545103
Source: PubMed

ABSTRACT Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney.

  • Source
    • "Focusing specifically on the impact of the renin angiotensin system, reciprocal cross-transplantations of fully vascularized kidney transplants between AT1A receptor deficient and wild type mice were performed to determine the relative importance of AT1A receptors expressed in renal (e.g., the renal epithelium, the renal vasculature or other renal components) and extra-renal (e.g., the resistance vasculature, the CNS or the adrenals) tissues for baseline blood pressure and angiotensin II induced hypertension. These studies support that the hypertensive effects of angiotensin II are predominantly dependent on renal AT1A receptors (Crowley et al., 2006). In contrast, the reduced resting blood pressure observed in AT1A deficient "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies and physiological investigations have linked alterations in acid-base transporters to hypertension. Accordingly, Na(+)-coupled HCO(-) 3-transporters, Na(+)/H(+)-exchangers, and anion-exchangers have emerged as putative mechanistic components in blood pressure disturbances. Even though hypertension has been studied extensively over the last several decades, the cause of the high blood pressure has in most cases not been identified. Renal, cardiovascular, and neuronal dysfunctions all seem to play a role in hypertension development but their relative importance and mutual interdependency are still being debated. Multiple functional and structural alterations have been described in patients and animals with hypertension but it is typically unclear whether they are causes or consequences of hypertension or represent mechanistically unrelated associations. Perturbed blood pressure regulation has been demonstrated in several animal models with disrupted expression of acid-base transporters; and reciprocally, disturbed acid-base transport function has been described in hypertensive individuals. In addition to regulating intracellular and extracellular pH, Na(+)-coupled HCO(-) 3-transport, Na(+)/H(+)-exchange, and anion-exchange also contribute to water and electrolyte balance in cells and systemically. Since acid-base transporters are widely expressed, alterations in transport activities likely affect multiple cell and organ functions, and it is a significant challenge to determine the mechanisms linking perturbed acid-base transport function to hypertension. It is the purpose of this review to evaluate the current evidence for involvement of acid-base transporters in hypertension development and discuss the cellular and integrative mechanisms, which may link changes in acid-base transport to blood pressure disturbances.
    Frontiers in Physiology 12/2013; 4:388. DOI:10.3389/fphys.2013.00388 · 3.50 Impact Factor
  • Source
    • "The production of Ang 1-7 by BeWo cells in the absence of prorenin raises the interesting possibility that non-renin proteases exist, which can form Ang peptides within human intrauterine tissues. As far as we know this possibility has not been investigated, although a non-renin angiotensin system (chymase) has been described in the heart where Ang II plays a key role in cardiac hypertrophy [32]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The renin-angiotensin system (RAS) is implicated in placentation. We determined which RAS pathways are present in two trophoblast cell lines (HTR-8/SVneo and BeWo cells) and the effects of cAMP, which stimulates renal renin. The effect of cAMP on RAS gene expression and on prorenin and angiotensin peptides in HTR-8/SVneo and BeWo cells were investigated. In HTR-8/SVneo cells, prorenin mRNA (REN) and protein, (pro)renin receptor (ATP6AP2) and angiotensin II type 1 receptor (AGTR1) were stimulated by cAMP (P < 0.05, P < 0.05, P < 0.001 and P < 0.05, respectively). HTR-8/SVneo cells also expressed angiotensinogen (AGT) and angiotensin converting enzyme 1 (ACE1), but did not express AGTR2 or ACE2 nor the Ang 1-7 receptor (MAS1). BeWo cells did not express REN, and REN was not inducible by cAMP, but cAMP increased ACE2 and MAS1 (both P < 0.05) and decreased AGT (P < 0.05). BeWo cells expressed AGT, ACE1, ACE2 and MAS1 but not ATP6AP2, AGTR1 nor AGTR2. There was net destruction of Ang II in media from HTR-8/SVneo and BeWo incubations and net production of Ang 1-7 by BeWo and untreated HTR-8/SVneo cells. HTR-8/SVneo cells express REN and produce prorenin as well as expressing other RAS genes likely to regulate Ang II/AT(1)R interactions and respond to cAMP, like renal renin-secreting cells. They are more similar to early gestation placentae and are therefore useful for studying effects of renin/ACE/Ang II/AT(1)R on cell function. BeWo cells express the ACE2/Ang 1-7/Mas pathway, which is sensitive to cAMP and therefore are useful for studying the effects of ACE2/Ang 1-7/Mas on trophoblast function.
    Placenta 05/2012; 33(8):634-9. DOI:10.1016/j.placenta.2012.05.001 · 3.29 Impact Factor
  • Source
    • "Measurements of sodium balance were carried out as described previously (Crowley et al., 2006) with individual metabolic cages and a gel diet containing nutrients, water, and 0.1% w/w sodium (Nutra-Gel; Bio-Serv, Frenchtown, NJ). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypertension affects more than 1.5 billion people worldwide but the precise cause of elevated blood pressure (BP) cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers BP in the majority of patients with hypertension. Despite its apparent role in hypertension pathogenesis, the key cellular targets of the RAS that control BP have not been clearly identified. Here we demonstrate that RAS actions in the epithelium of the proximal tubule have a critical and nonredundant role in determining the level of BP. Abrogation of AT(1) angiotensin receptor signaling in the proximal tubule alone is sufficient to lower BP, despite intact vascular responses. Elimination of this pathway reduces proximal fluid reabsorption and alters expression of key sodium transporters, modifying pressure-natriuresis and providing substantial protection against hypertension. Thus, effectively targeting epithelial functions of the proximal tubule of the kidney should be a useful therapeutic strategy in hypertension.
    Cell metabolism 04/2011; 13(4):469-75. DOI:10.1016/j.cmet.2011.03.001 · 16.75 Impact Factor
Show more


Available from