Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation Research. 2006;99:1285-1286
doi: 10.1161/01.RES.0000253141.65450.fc
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by De Mello, W. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Mello, W. C.
Related Collections
Right arrowRelated Article
(Circulation Research. 2006;99:1285.)
© 2006 American Heart Association, Inc.

Editorials

On the Pathophysiological Implications of an Intracellular Renin Receptor

Walmor C. De Mello

From the School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan.

Correspondence to Walmor C. De Mello, Medical Sciences Campus, School of Medicine, PO Box 36–5067, San Juan, PR 00936-5067, USA. E-mail wmello{at}rcm.upr.edu



See related article, pages 1355–1366


Key Words: intracellular • renin • receptor • patophysiological • implications

The renin angiotensin system plays an important role on the regulation of arterial pressure, blood volume and cardiac function. Both a circulating and several tissue-localized systems have been identified and able to cleave angiotensinogen by renin to form angiotensin I which is converted to angiotensin II (Ang II) by angiotensin converting enzyme. The presence of local Ang II generation, which has been supported by the beneficial effects of Ang II AT1 receptor blockers and ACE inhibitors independently of their effects on arterial blood pressure, certainly requires that renin, angiotensinogen and ACE be synthesized locally or taken from the plasma.

Concerning the presence of the different components of the RAS in different tissues1 evidence is available that in nephrectomized rats, the renin levels in the heart, for instance, are extremely low2 what indicates that intracellular renin in cardiac myocytes of normal animals, would need to come from plasma. However, rats transgenic for the mouse ren-2d renin gene develop severe hypertension and cardiac remodeling3 and incubation of cardiac myocytes from these animals with prorenin (the precursor of renin) leads to intracellular appearance of angiotensin I and II3 what suggests prorenin internalization. Moreover, an alternative transcript for a nonsecreted renin has been described in brain and heart.4,5 The transfection of a nonsecreted form of angiotensinogen into hepatoma cells that expressed this renin transcript, increased proliferation by a process that is sensitive to renin antisense,6 indicating that the renin transcript has functional properties. Indeed, the alternative renin trancript is upregulated in adult rats with MI suggesting its contribution to intracellular Ang II generation under pathological conditions.7 Regardless of whether intracellular renin or Ang II is the result of intracellular synthesis or internalization, evidence exists that intracellular renin is able to increment the inward calcium current in myocytes from the failing heart.8 In addition, transgenic overexpression of the intracellular nonsecreted form of renin and angiotensinogen in the brain leads to an increase in drinking volume and mean arterial pressure.9 The work of Schefe et al10 indicated that the primary localization of the human renin/prorenin receptor (RER) is in the perinuclear zone what conflicts with previous studies indicating its localization in the plasma cell membrane.11 The intracellular localization was confirmed using different constructs and studies of mutagenesis and colocalization. Indeed, mutagenesis of the atypical C-terminal ER-retention signal strongly reduced the perinuclear localization of the renin receptor.10 Furthermore, a transcription factor promyelocytic zinc finger protein (PLZF) was identified as a direct protein interaction partner of the C-terminal domain of the renin receptor and following the activation of RER by renin, PLZF is translocated from the cytoplasm to the nucleus providing positive or negative regulation of target genes.10 Renin stimulation also increased PI3-K-85{alpha} messenger RNA whereas small interfering RNA against PLZF abolished this effect10. Moreover, experiments performed on PLZF knockout mice supported the view that PLZF is an upstream regulator of RER10. Interestingly, renin stimulation in rat H9c2 cardiomyoblasts not only increased the cell number but elicited a decrease of apoptosis.10

Although further studies will be needed to rule out the existence of more than 1 renin receptor, Schefe et al10 did not rule out the possibility that very small amount of RER within the plasma cell membrane might be sufficient to initiate a RER signal transduction cascade despite its intracellular localization. In this case, other receptors like mannose-6 phosphate receptors could internalize renin and prorenin12 and the intracellular Ang II formation elicited by renin internalization, might explain the severe cardiac damage seen in transgenic rats expressing the mouse ren-2d renin gene.13

The question remains whether renin is able to work by itself or depends on the formation of Ang II. Tissue accumulation of plasma prorenin results in angiotensin generation14 but could also, through binding to a recently cloned prorenin/renin receptor, lead to angiotensin-independent effects including p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI-1) release15. In mesangial cells, renin increases transforming growth factor-ß 1 and matrix proteins also independently of Ang II mechanisms16 whereas in cardiomyocytes isolated from the failing heart, intracellular renin increments the inward calcium current, an effect suppressed by intracellular losartan.8 These apparent discrepant results lead us to think that the activation of RER has multiple functions some related to the activation of the RAS and other not (see Figure). Here caution must be exercised because variations of species or type of preparations used in the experiments might influence the results.


Figure 1
View larger version (16K):
[in this window]
[in a new window]

  		Diagram illustrating the activation of RER by intracellular renin and the displacement of the transcription factor (PLZF) to the nucleus with regulation of target genes(see Schefe et al10). Possible sources of intracellular renin include renin internalization, a nonsecreted isoform of renin or the enhanced expression of the renin gene elicited by different pathological conditions involving stretch. The diagram also shows the possible generation of Ang II inside the cell and its effect decreasing gap junctional communication and increasing the inward calcium current.

The intracellular localization of the renin receptor described in Schefe’s article10 certainly reactivates the tantalized question whether an intracellular renin angiotensin system is involved on the regulation of tissue function in different pathophysiological conditions. Activation of this receptor by enhanced expression of renin gene elicited by cell stretch17 for instance, might be in part responsible for cardiac remodeling and changes in electrical properties.23,1 On the other hand, increased internalization of renin can result in intracellular degradation18 or intracellular angiotensin generation.3,8

The clinical implications of these findings are several: 1) inhibition of prorenin binding attenuates the development and progression of cardiac fibrosis19 and inhibits the development of diabetic nephropathy in animal models20; 2) RER messenger RNA can be detected in human glioblastomas and renin inhibitors decreases the number of cells in glioblastoma cell lines21; 3) a mutation of the renin receptor gene causes the X-linked mental retardation and epilepsy in humans22; and 4) intracellular renin reduces cell communication in the heart, an effect drastically reduced by intracellular enalaprilat.23 It is, then, conceivable that stimulation of RER by overexpression of the renin gene might impair impulse propagation and facilitates the generation of cardiac arrhythmias.

As it can be seen, the intricacies of the RER activation and possible consequences are barely realized. The widespread implications of RER in different pathological conditions as described above, support the view that the biological relevance of this receptor goes beyond the RAS. Cytoplasmic compartmentalization and the activation of a variety of intracellular signal pathways as well positive or negative regulation of target genes might be responsible for the diverse pathophysiological implications related to the activation of RER. Future research in this area promises to bring far more penetrating insights into the intracellular renin receptor and it will help to develop specific RER inhibitors.


*    Acknowledgments
 
Sources of Funding

This work was supported by grants HL 34148 and G12RR-03051 from NIH.

Disclosures

None.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 *References
 

  1. Kurdi M, De Mello WC, Booz GW. Working outside the system: an uptodate on the unconventional behavior of the renin angiotensin system components. Intern J Biochem Cell Biol. 2005; 37: 1357–1367.[CrossRef][Medline] [Order article via Infotrieve]
  2. Katz SA, Opsahl JA, Lunzer MM, Forbis LM, Hirsh AT. Effect of bilateral nephrectomy on active renin, angiotensinogen and renin glycoforms in plasma and myocardium. Hypertension. 1997; 30: 259–266.[Abstract/Free Full Text]
  3. Peters J, Farrenkopf R, Clausmeyer S, Zimmer J, Kantachuverisi S, Sharp MS, Mullins JJ. Functional significance of prorenin internalization in the rat heart. Circ Res. 2002; 90: 1135–1141.[Abstract/Free Full Text]
  4. Lee-Kirsch MA, Gaudet F, Cardoso MC, Lindpaintner K. Distinct renin isoforms generated by tissue-specific transcription initiation and alternative splicing. Circ Res. 1999; 84: 240–246.[Abstract/Free Full Text]
  5. Clausmeyer S, Sturzebecher R, Peters J. An alternative transcript of the renin gene can result in truncated prorenin that is transported into adrenal mitochondria. Circ Res. 1999; 84: 337–344.[Abstract/Free Full Text]
  6. Sherrod M, Liu X, Zhang X, Sigmund CD. Nuclear localization of angiotensinogen in astrocytes. Am J Physiol Regul Integr Comp Physiol. 2005; 288: R539–R546.[Abstract/Free Full Text]
  7. Clausmeyer SW, Reinecke A, Farrenkopf R, Unger T, Peters J. Tissue-specific expression of a rat renin transcript lacking the coding sequence for the prefragment and stimulation by myocardial infarction. Endocrinology. 2000; 141: 2963–2970.[Abstract/Free Full Text]
  8. De Mello WC. Renin increments inward calcium current in the failing heart. J Hypertens. 2006; 24: 1181–1186.[Medline] [Order article via Infotrieve]
  9. Lavoie JL, Liu X, Bianco RA, Beltz TG, Johnson AK, Sigmund CD. Evidence supporting a functional role of intracellular renin in the brain. Hypertension. 2006; 47: 461–466.[Abstract/Free Full Text]
  10. Schefe JH, Menk M, Reinemund J, Effertz K, Hobbs R, Pandolfi PP, Ruiz P, Unger T, Funke-Kaiser H. A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcriptor factor PLZF. Circ Res. 2006; 99: 1355–1366.[Abstract/Free Full Text]
  11. Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular reponses to renin. J Clin Invest. 2002; 109: 1417–27.[CrossRef][Medline] [Order article via Infotrieve]
  12. Danser AH, Deinum J Renin, prorenin and putative (pro)renin receptors. Hypertension. 2005; 46: 1069–1076.[Free Full Text]
  13. Kantachuverisi S, Fleming S, Peters J, Peters B, Brooker G, Lammie AG, McGrath I et al. Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. J Biol Chem. 2001; 276: 36727–33.[Abstract/Free Full Text]
  14. Prescott G, Silversides DW, Chiu SML, Reudelhuber TL. Contribution of circulating renin to local synthesis of angiotensin peptides in the heart. Physiological Genomics. 2000; 4: 67–73.[Abstract/Free Full Text]
  15. Saris JJ, Peter AC, ’t Hoen , Garrelds IM, Dekkers DHW, den Dunnen JT, Lamers JML, Jan Danser AH. Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. Hypertension. 2006; 48: 564–571.[Abstract/Free Full Text]
  16. Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens RT, Yu L, Noble NA, Border W. Renin increases mesangial cell transforming growth factor-beta 1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 2006; 69: 105–113.[CrossRef][Medline] [Order article via Infotrieve]
  17. Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993; 75: 977–984.[CrossRef][Medline] [Order article via Infotrieve]
  18. Saris JJ, Derbx FHM, de Bruin RJA, Dekkers DHW, Lamers JMJ, Saxena PR, et al. High affinity protein bind to cardiac man-6-P/IGF-II receptors precedes proteolytic activation to renin. Am J Physiol. 2001; 280: H1706–H1715.
  19. Ichihara A, Kaneshiro Y, Takemetzu T, Susuki F, Nakagama T, Nishiyama A et al Receptor-associated prorenin system contributes to hypertensive end-organ damage. J Hypertens. 2005; 23 (Suppl 2)S78: P71.197.
  20. Ichihara A, Hayashi K, Kaneshiro Y, Susuki F, Nakagawa T, Tada Y et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the << handle >> region for nonproteolytic activation of prorenin. J Clin Invest. 2004; 114: 1128–1135.[CrossRef][Medline] [Order article via Infotrieve]
  21. Juillerat-Jeanneret L, Celerier J, Chapnis Bernaconi C, Nguyen G, Wostl W, Marki HP et al. Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma. Br J Cancer. 2004; 90: 1059–1068.[CrossRef][Medline] [Order article via Infotrieve]
  22. Ramser J, Abidi FE, Burckle CA, Lenski C, Torielo H, Wen G et al. A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet. 2005; 14: 1019–1027.[Abstract/Free Full Text]
  23. De Mello WC. Influence of intracellular renin on heart cell communication. Hypertension. 1995; 25: 1172–1177.[Abstract/Free Full Text]

Related Article:

A Novel Signal Transduction Cascade Involving Direct Physical Interaction of the Renin/Prorenin Receptor With the Transcription Factor Promyelocytic Zinc Finger Protein
Jan H. Schefe, Mario Menk, Jana Reinemund, Karin Effertz, Robin M. Hobbs, Pier Paolo Pandolfi, Patricia Ruiz, Thomas Unger, and Heiko Funke-Kaiser
Circ. Res. 2006 99: 1355-1366. [Abstract] [Full Text] [PDF]



This article has been cited by other articles:


Home page
 HypertensionHome page
E. D. Frohlich
The Salt Conundrum: A Hypothesis
Hypertension, July 1, 2007; 50(1): 161 - 166.
[Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by De Mello, W. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Mello, W. C.
Related Collections
Right arrowRelated Article

Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2006 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.