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: 9.67). 12/2006; 103(47):17985-90. DOI: 10.1073/pnas.0605545103
Source: PubMed


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.

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    • "Previous reports have shown that during the first 3 days of AngII infusion, even at a higher infusion doses, blood pressure is not significantly elevated compared to sham-operated animals (Zou et al. 1996; Kawada et al. 2002; Gonzalez et al. 2014). Therefore, in our study, hypertension is not expected, and there was no pressure diuresis or natriuresis, no cardiac hypertrophy, and no change in hematocrit, thus, no evidence for acute volume expansion or hypertension, also no AngII associated reduced rate of weight gain, nor change in hematocrit, all previously reported by us and others during weeks long infusion of AngII (Crowley et al. 2006; Ortiz et al. 2007; Semprun- Prieto et al. 2011; Nguyen et al. 2013). Finally, AngII infusion did not significantly change plasma [Na + ] or [K + ] indicating that electrolyte balance was maintained. "
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    ABSTRACT: In Sprague Dawley rats, 2-week angiotensin II (AngII) infusion increases Na(+) transporter abundance and activation from cortical thick ascending loop of Henle (TALH) to medullary collecting duct (CD) and raises blood pressure associated with a pressure natriuresis, accompanied by depressed Na(+) transporter abundance and activation from proximal tubule (PT) through medullary TALH. This study tests the hypothesis that early during AngII infusion, before blood pressure raises, Na(+) transporters' abundance and activation increase all along the nephron. Male Sprague Dawley rats were infused via osmotic minipumps with a subpressor dose of AngII (200 ng/kg/min) or vehicle for 3 days. Overnight urine was collected in metabolic cages and sodium transporters' abundance and phosphorylation were determined by immunoblotting homogenates of renal cortex and medulla. There were no significant differences in body weight gain, overnight urine volume, urinary Na(+) and K(+) excretion, or rate of excretion of a saline challenge between AngII and vehicle infused rats. The 3-day nonpressor AngII infusion significantly increased the abundance of PT Na(+)/H(+) exchanger 3 (NHE3), cortical TALH Na-K-2Cl cotransporter 2 (NKCC2), distal convoluted tubule (DCT) Na-Cl cotransporter (NCC), and cortical CD ENaC subunits. Additionally, phosphorylation of cortical NKCC2, NCC, and STE20/SPS1-related proline-alanine-rich kinase (SPAK) were increased; medullary NKCC2 and SPAK were not altered. In conclusion, 3-day AngII infusion provokes PT NHE3 accumulation as well as NKCC2, NCC, and SPAK accumulation and activation in a prehypertensive phase before evidence for intrarenal angiotensinogen accumulation.
    09/2015; 3(9). DOI:10.14814/phy2.12496
    • "Evidence from animal and clinical studies with angiotensinconverting enzyme inhibitors and antagonists of angiotensin II (Ang II) type 1 receptors (AT 1 Rs) identified the Ang II/AT 1 receptor pathway as a major cause of cardiac damage (de Gasparo et al., 2000; López-Sendón et al., 2004; Higuchi et al., 2007; McMurray et al., 2012; Elliott et al., 2014). Kidney crosstransplantation experiments in gene-targeted mice suggest that selective ablation of renal AT 1 Rs prevents adverse cardiac remodeling, whereas AT 1 Rs in the heart are not involved in the Ang II–stimulated stress response, i.e., pathologic growth of cardiomyocytes (CMs) and fibrosis (Crowley et al., 2006). In contrast, different rodent models that overexpress the AT 1 R in CMs reportedly developed This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Research Unit 2060 " cGMP signaling in cell growth and survival " with grants to R.L., A.F., and V.O.N. and by the Elite Programme financed by the Landesstiftung Baden-Württemberg (to R.L.). "
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    ABSTRACT: Analyses of several mouse models imply that the phosphodiesterase 5 (PDE5) inhibitor sildenafil (SIL), via increasing cyclic guanosine-3',5'-monophosphate (cGMP), affords protection against angiotensin II (AngII) stimulated cardiac remodeling. However, it is unclear which cell types are involved in these beneficial effects, because AngII may exert its adverse effects by modulating multiple reno-vascular and cardiac functions via AngII type 1 receptors (AT1R). To test the hypothesis that SIL/cGMP oppose cardiac stress provoked by amplified AngII/AT1R directly in cardiomyocytes (CMs), we studied transgenic mice with CM-specific overexpression of the AT1R under the control of the α-myosin-heavy chain promoter (αMHC-AT1Rtg/+). The extent of cardiac growth was assessed in absence or presence of SIL and defined by referring changes in heart-weight to body-weight or tibia length. Hypertrophic marker genes, extracellular matrix-regulating factors and expression patterns of fibrosis markers were examined in αMHC-AT1Rtg/+ ventricles (±SIL) and corroborated by investigating different components of the natriuretic peptide (NP)/PDE5/cGMP pathway as well as cardiac functions. cGMP levels in heart lysates and intact CMs were measured by competitive immunoassays and FRET. We find higher cardiac and CM cGMP levels and up-regulation of the cGMP-dependent protein kinase I (cGKI) with AT1R over-expression. However, even a prolonged SIL treatment regimen did not limit the progressive CM growth, fibrosis or decline in cardiac functions in the αMHC-AT1Rtg/+ model suggesting that SIL does not interfere with the pathogenic actions of amplified AT1R signaling in CMs. Hence, the cardiac/non-cardiac cells involved in the cross-talk between SIL-sensitive PDE activity and AngII/AT1R need to be identified. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 07/2015; 354(3). DOI:10.1124/jpet.115.226092 · 3.97 Impact Factor
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    • "Protein restriction during gestation programmed the downregulation of signaling components of the RAS with effects on blood pressure [7], [48], and this seems also to be the case for chronic protein deprivation through eating BRD after weaning. It has been demonstrated that RAS is important in the pathological heart hypertrophy [49], [50] that is counteracted by blocking AT1R [51] with simultaneous prevention of cardiac electric remodeling [52]. The view that kidney receptors are associated with heart receptors in the cardiac structural and electric remodeling receives further support from the observation that elimination of AT1R in mice reduces cardiac hypertrophy and the risk of hypertension [49], and also from the observation that primary renal dysfunction in rats is associated with an augmented risk of congestive cardiac failure in simultaneous alterations that constitute a cardiorenal syndrome [53]. "
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    ABSTRACT: Background Several studies have correlated protein restriction associated with other nutritional deficiencies with the development of cardiovascular and renal diseases. The driving hypothesis for this study was that Ang II signaling pathways in the heart and kidney are affected by chronic protein, mineral and vitamin restriction. Methodology/Principal Findings Wistar rats aged 90 days were fed from weaning with either a control or a deficient diet that mimics those used in impoverished regions worldwide. Such restriction simultaneously increased ouabain-insensitive Na+-ATPase and decreased (Na++K+)ATPase activity in the same proportion in cardiomyocytes and proximal tubule cells. Type 1 angiotensin II receptor (AT1R) was downregulated by that restriction in both organs, whereas AT2R decreased only in the kidney. The PKC/PKA ratio increased in both tissues and returned to normal values in rats receiving Losartan daily from weaning. Inhibition of the MAPK pathway restored Na+-ATPase activity in both organs. The undernourished rats presented expanded plasma volume, increased heart rate, cardiac hypertrophy, and elevated systolic pressure, which also returned to control levels with Losartan. Such restriction led to electrical cardiac remodeling represented by prolonged ventricular repolarization parameters, induced triggered activity, early after-depolarization and delayed after-depolarization, which were also prevented by Losartan. Conclusion/Significance The mechanisms responsible for these alterations are underpinned by an imbalance in the PKC- and PKA-mediated pathways, with participation of angiotensin receptors and by activation of the MAPK/ERK1/2 pathway. These cellular and molecular alterations culminate in cardiac electric remodeling and in the onset of hypertension in adulthood.
    PLoS ONE 07/2014; 9(7):e100410. DOI:10.1371/journal.pone.0100410 · 3.23 Impact Factor
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