Nuclear angiotensin-(1–7) receptor is functionally coupled to the formation of nitric oxide

Gwathmey, TanYa M.; Westwood, Brian; Pirro, Nancy T.; Tang, Lijun; Rose, James C.; Diz, Debra I.; Chappell, Mark C.

doi:10.1152/ajprenal.00371.2010

Cited by 75 publications

(101 citation statements)

References 45 publications

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“…Indeed, it has been postulated that ACE2 is renoprotective due to its highly specific action to generate Ang-(1-7) from Ang II (21,38,59,61,62). In the kidney, the highest levels of ACE2 and the proposed Ang-(1-7) binding site are found in cortical proximal tubules (13,27,40,62). This is consistent with our results suggesting that ACE2-dependent Ang-(1-7) formation occurs mainly in renal cortex.…”

Section: Discussionsupporting

confidence: 92%

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Grobe

Elased

Cool

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Grobe N, Elased KM, Cool DR, Morris M. Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney. Am J Physiol Endocrinol Metab 302: E1016 -E1024, 2012. First published February 7, 2012 doi:10.1152/ajpendo.00515.2011.-To better understand the tissue distribution and activity of enzymes involved in angiotensin II (Ang II) processing, we developed a novel molecular imaging method using matrix-assisted laser desorption ionizationtime-of-flight (MALDI-TOF) mass spectrometry. Mouse kidney sections (12 m) were incubated with 10 -1,000 mol/l Ang II for 5-15 min at 37°C. The formed peptides Ang III and Ang-(1-7) were identified by MALDI-TOF/TOF. A third metabolite, Ang-(1-4), was generated from further degradation of Ang-(1-7). Enzymatic processing of Ang II was dose and time dependent and absent in heat-treated kidney sections. Distinct spatial distribution patterns (pseudocolor images) were observed for the peptides. Ang III was localized in renal medulla, whereas Ang-(1-7)/Ang-(1-4) was present in cortex. Regional specific peptide formation was confirmed using microdissected cortical and medullary biopsies. In vitro studies with recombinant enzymes confirmed activity of peptidases known to generate Ang III or Ang-(1-7) from Ang II: aminopeptidase A (APA), Ang-converting enzyme 2 (ACE2), prolyl carboxypeptidase (PCP), and prolyl endopeptidase (PEP). Renal medullary Ang III generation was blocked by APA inhibitor glutamate phosphonate. The ACE2 inhibitor MLN-4760 and PCP/PEP inhibitor Z-pro-prolinal reduced cortical Ang-(1-7) formation. Our results establish the power of MALDI imaging as a highly specific and information-rich analytical technique that will further aid our understanding of the role and site of Ang II processing in cardiovascular and renal pathologies. matrix-assisted laser desorption ionization imaging; angiotensin-converting enzyme 2; prolyl carboxypeptidase; prolyl endopeptidase; aminopeptidase A THE POTENT VASOCONSTRICTOR ANGIOTENSIN II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS), controlling renal function and blood pressure. Inhibitors of Ang II synthesis and receptor binding are commonly used in the management of hypertension, congestive heart failure, and renal disease. However, there is growing evidence that therapeutic interventions targeting receptor binding and peptide generation have not provided as much cardiovascular risk reduction as anticipated (1, 56). The search for treatment alternatives continues, particularly since reports have emerged of novel Ang II binding sites as well as reactivation of Ang II synthesis after chronic treatment with Ang-converting enzyme (ACE) inhibitors (4, 32,41,44). Ang II degradation might be a target for potential new treatment strategies against Ang II's vasoconstrictive actions (16,42). However, this requires a reliable method to assess Ang II processing enzyme activities, particularly in pathological states shown to be associated with up/downregulation of RAS enzymes (7,15,59,61). Recognizing the ad...

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Section: Discussionsupporting

confidence: 92%

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Grobe

Elased

Cool

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…The data in that study also showed that the biphasic effect of ANG-(1-7) on the Na+/H+ exchanger occurred via the Mas receptor and that A779 (a Mas receptor antagonist) abolished this hormonal biphasic effect. These results are also consistent with previously described findings in the literature that indicated that the renal effects of ANG-(1-7) are dose dependent and mediated, at least in part, by the Mas receptor [193][194][195][196]. Nevertheless, in isolated rat proximal straight tubules (S3 segment), it was shown that, like ANG II, ANG-(1-7) exerts a biphasic effect through AT1 receptors: at physiological levels, ANG-(1-7) increases fluid and bicarbonate reabsorption, while at high concentrations, ANG-(1-7) decreases these parameters [183].…”

Section: Actions Of Ang-(1-7) In the Kidneysupporting

confidence: 93%

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

Mello-Aires¹,

Dellova²,

Castelo‐Branco³

et al. 2017

Nephrol Renal Dis

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This article reviews the main body of knowledge regarding NHE1 and NHE3 exchangers and their interaction with Angiotensin II, Angiotensin-(1-7), Aldosterone and Arginine Vasopressin, particularly their renal actions. This work addresses the biphasic effects of different hormonal doses on NHE1 or NHE3 in proximal tubule in Wistar, SHR (hypertensives) and their control WKY (normotensives) rats or MDCK cells (which share similarities with the collecting duct). The hormones were applied alone, with their inhibitors or plus agents that change the [Ca 2+ ]i. The data are compatible with hormonal stimulation of these exchangers by increases of [Ca 2+ ]i in lower range, and inhibition at high [Ca 2+ ]i. In MDCK cells and Wistar rats, low doses of ANG II, ALDO or AVP stimulated the exchangers, while high doses inhibited them. ANG-(1-7), in Wistar or WKY rats has inverse, dose-dependent effects. In SHR rats, the biphasic effects of ANG-(1-7) were similar to the effects of ANG II, ALDO or AVP in Wistar rats. The interactions between these effects may represent a mechanism that regulates extracellular volume. In hypertensives animals, a high plasma level of ANG-(1-7) inhibited NHE3 in the proximal tubule, which mitigated hypertension. Figure 6 shows a schematic model to describe these biphasic hormonal effects.

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“…3F). A similar approach was taken for the AT 7 /Mas receptor in isolated nuclei of the sheep kidney (55)(56)(57)(58). An alomone antibody (Alomone Labs, Tel Aviv, Israel) revealed Mas receptor expression along the tubular elements of the kidney that was abolished by antibody preabsorption with the immunogenic peptide; a single band (ϳ35 kDa) was evident on the full-length immunoblot of isolated nuclei (Fig.…”

Section: Ras Protein Componentsmentioning

confidence: 97%