A new cardiac MASTer switch for the renin-angiotensin system

The aspartyl protease renin was first isolated from the kidney by Tigerstedt more than a century ago. In the kidney, renin secretion is tightly linked to sodium intake and renal perfusion pressure, reflecting the important role of the renin-angiotensin system (RAS) in controlling body fluid volume and blood pressure. The study by Mackins et al. in this issue of the JCI describes a novel source of renin: the mast cell (see the related article beginning on page 1063). This discovery suggests a distinct pathway for activation of the RAS that may have a particular impact on the pathogenesis of chronic tissue injury as well as more acute pathology such as arrhythmias in the heart.

The renin-angiotensin system (RAS) is a hormone system in which the substrate protein angiotensinogen is sequentially cleaved by peptidases, renin and angiotensin-converting enzyme (ACE), to form the biologically active octapeptide angiotensin II (Figure 1). A substantial excess of angiotensinogen is present in serum, and ACE is ubiquitous in the endothelium and plasma (1). Accordingly, in the bloodstream, the amount of renin is the rate-limiting step determining the level of angiotensin II and thus the activity of the system.

Figure 1

Production of renin by cardiac mast cells represents a novel mechanism for regulating the RAS. In this issue of the JCI, Mackins, Levi, and associates show that ischemia of the heart triggers renin release by cardiac mast cells, resulting in activation of the RAS (11). The consequent production of angiotensin II stimulates angiotensin II receptor, type 1 (AT₁) in sympathetic nerve terminals, causing release of norepinephrine (NE) and generation of cardiac arrhythmias. These studies indicate that resident mast cells in the heart and perhaps other organs, upon appropriate stimulation, are capable of producing ample quantities of renin to activate the RAS locally and thereby modulate organ function. This pathway is likely to be regulated by factors linked to inflammation and injury that are quite different from those controlling renin release at the JG apparatus of the kidney. NHE, Na⁺/H⁺ exchanger.

The primary source of renin in the circulation is the kidney, where its expression and secretion are tightly regulated at the juxtaglomerular (JG) apparatus by 2 distinct mechanisms: a renal baroreceptor (2, 3) and sodium chloride delivery to the macula densa (4, 5). Through these sensing mechanisms, levels of renin in plasma can be incrementally titrated in response to changes in blood pressure and salt balance. These regulatory principles provide a basis for many of the physiological characteristics of the RAS. Yet there appears to be additional complexity in the system. For example, in the broad population of patients with hypertension, diabetes, and cardiovascular disease, pharmacological antagonists of the RAS lower blood pressure and prevent end-organ damage even in the absence of overt elevation of plasma renin levels.

In response to these apparent discrepancies, the concept was articulated some years ago that individual tissues might have their own local RASs, which could be regulated independently of the circulating system (6). This theory is supported by studies demonstrating expression of RAS genes in a variety of key target organs, including the heart and brain (7, 8). Moreover, control of RAS gene expression has been found to differ significantly among organs (9), indicating a potential basis for autonomy of these tissue systems.

Although expression of angiotensinogen, ACE, and angiotensin receptors has been clearly demonstrated in a variety of organ systems (7), it has been more difficult to convincingly document physiologically relevant expression of renin outside the kidney. This has presented a challenge to the concept of complete and autonomous RASs in individual tissues. Studies by Mackins, Levi, and colleagues indicating that mast cells generate and secrete renin (10, 11) may provide a solution to this problem. In a previous article, these authors reported that mast cells express renin mRNA and contain significant quantities of renin protein, likely within secretory granules (10). When degranulation of the mast cells was induced, renin derived from mast cells specifically and efficiently converted angiotensinogen to angiotensin I (10). Using an isolated, perfused heart preparation, they have now, in this issue of the JCI, extended the previous studies by showing that release of renin from cardiac mast cells causes local formation of angiotensin in sufficient amounts to cause pathophysiological consequences including release of norepinephrine and generation of arrhythmias (11) (Figure 1). Taken together, these studies provide compelling evidence that resident mast cells in the heart and perhaps other organs, upon appropriate stimulation, are capable of generating ample quantities of renin to activate the RAS locally and thereby affect organ function.

Mast cells are derived from hematopoietic progenitors that migrate into all vascularized tissues, where they mature and reside, constituting an important effector limb of the inflammatory response (12). Upon activation, mast cells undergo complex biochemical and morphological alterations culminating in the release of a wide range of mediators from cytoplasmic granules. The work of Mackins, Levi, and associates indicates that renin is one of the mediators released with degranulation (10, 11). However, the precise basis for control of renin in mast cells is not clear, and this will be a critical area for future research. It is notable that renin is also stored in secretory granules within renal JG cells, where it is released through degranulation and exocytosis (1, 13). Yet despite the apparent similarities in the intracellular machinery for handling renin, the regulatory factors and pathways controlling renin in JG cells and mast cells are likely to be quite different.

The prototypical pathway for mast cell activation and degranulation involves engagement of FcεRI receptors by antibody or immune complexes, with activation of phospholipase C and increases in intracellular calcium concentration (12). By contrast, exocytosis of renin granules in JG cells is linked to G_S protein signaling and increases in intracellular cAMP levels (14). Mackins et al. now show that ischemia in isolated guinea pig hearts perfused with a blood-free solution is sufficient to stimulate cardiac mast cells to release renin (11). Thus, cardiac mast cells appear to be capable of secreting renin through a process that is independent of typical antibody-receptor triggering. While the specific factors controlling renin release by mast cells have not yet been identified, a number of stimuli that are potentially relevant to cardiovascular disease can modulate mast cell degranulation, including cytokines, prostaglandins, adenosine, and LPS (12, 15, 16). Thus, it is likely that the pathway controlling renin release in tissues will be linked to environmental cues associated with inflammation and injury (Figure 1).

Although the finding that mast cells are a source of renin in peripheral tissues is novel (11), previous studies have suggested a role for cardiac mast cells in the RAS. It has been long recognized that there are alternate pathways for converting angiotensin I to angiotensin II that do not require ACE. A clinical consequence of these pathways is seen in patients who take ACE inhibitors chronically, where incomplete suppression of angiotensin II levels in plasma is often observed (17). ACE-independent angiotensin II formation was found to be particularly robust in the heart, and this activity was eventually assigned to a serine proteinase belonging to the chymase family (18). Furthermore, the major cellular source of this chymase is the mast cell (19) (Figure 1). With the discovery of renin in mast cells, it is now apparent that these cells have the complete enzymatic machinery to produce angiotensin II from angiotensinogen. Why would mast cells have this capacity? While the answer to the question is not clear, one function of mast cells is immunoregulation (12). As angiotensin II itself can modulate inflammation and immunity (20), one purpose for renin generated by mast cells may be immunomodulation through regulating the activity of the RAS in the immune system.

The strongest evidence for a connection between mast cells and human disease is in the area of allergic diseases and asthma. However, mast cells may also be involved in a spectrum of inflammatory diseases ranging from multiple sclerosis, migraine, inflammatory arthritis, atopic dermatitis, interstitial cystitis, irritable bowel syndrome, and coronary inflammation (21). In the heart, mast cells accumulate in coronary plaques at the site of plaque rupture in myocardial infarction (22, 23), and the number of degranulated mast cells in the adventitia surrounding ruptured plaques is increased in infarct-related coronary arteries (24). In these circumstances, release of renin by mast cells and subsequent activation of the RAS in the heart might contribute directly to the pathogenesis of cardiac injury. Consistent with this idea, a recent study indicates a direct role for mast cells in promoting left-ventricular dysfunction in a model of congestive heart failure (25).

In summary, the finding that mast cells produce renin raises the possibility of an alternate mechanism for regulation of the RAS, controlled by inflammatory mechanisms likely to be quite different from those that regulate renin release by the kidney. Moreover, this mast cell–dependent pathway for renin production may be linked to local activation of the RAS in the heart, and perhaps other organs, potentially providing a distinct control for angiotensin II generation in peripheral tissues. A critical question, which can be tested with available tools, is whether this alternative pathway for RAS activation plays any major role in physiology or disease pathogenesis. If so, this pathway would represent a tangible link between inflammation, the RAS, and cardiovascular disease.

Nonstandard abbreviations used: ACE, angiotensin-converting enzyme; JG, juxtaglomerular; RAS, renin-angiotensin system.

Conflict of interest: The authors have declared that no conflict of interest exists.

See the related article beginning on page 1063.

1. Peach, M.J. 1977. Renin-angiotensin system: biochemistry and mechanisms of action. Physiol. Rev. 57:313-370.
   View this article via: PubMed Google Scholar
2. Bock, H.A., Hermle, M., Brunner, F.P., Thiel, G. 1992. Pressure dependent modulation of renin release in isolated perfused glomeruli. Kidney Int. 41:275-280.
   View this article via: PubMed Google Scholar
3. Carey, R.M., McGrath, H.E., Pentz, E.S., Gomez, R.A., Barrett, P.Q. 1997. Biomechanical coupling in renin-releasing cells. J. Clin. Invest. 100:1566-1574.
   View this article via: JCI PubMed Google Scholar
4. Bell, P.D., et al. 2003. Macula densa cell signaling involves ATP release through a maxi anion channel. Proc. Natl. Acad. Sci. U. S. A. 100:4322-4327.
   View this article via: PubMed Google Scholar
5. Lorenz, J.N., Greenberg, S.G., Briggs, J.P. 1993. The macula densa mechanism for control of renin secretion. Semin. Nephrol. 13:531-542.
   View this article via: PubMed Google Scholar
6. Dzau, V.J. 1987. Implications of local angiotensin production in cardiovascular physiology and pharmacology. Am. J. Cardiol. 59:59A-65A.
7. Bader, M., et al. 2001. Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research. J. Mol. Med. 79:76-102.
   View this article via: PubMed Google Scholar
8. Davisson, R.L. 2003. Physiological genomic analysis of the brain renin-angiotensin system. Am. J. Physiol. 285:R498-R511.
9. Dostal, D.E., Baker, K.M. 1999. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ. Res. 85:643-650.
   View this article via: PubMed Google Scholar
10. Silver, R.B., et al. 2004. Mast cells: a unique source of renin. Proc. Natl. Acad. Sci. U. S. A. 101:13607-13612.
    View this article via: PubMed Google Scholar
11. Mackins, C.J., et al. 2006. Cardiac mast cell–derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J. Clin. Invest. 116:1063-1070.
    View this article via: CrossRef PubMed Google Scholar
12. Galli, S.J., et al. 2005. Mast cells as a “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23:749-786.
    View this article via: PubMed Google Scholar
13. Peti-Peterdi, J., Fintha, A., Fuson, A.L., Tousson, A., Chow, R.H. 2004. Real-time imaging of renin release in vitro. Am. J. Physiol. 287:F329-F335.
14. Kurtz, A., Wagner, C. 1999. Cellular control of renin secretion. J. Exp. Biol. 202:219-225.
    View this article via: PubMed Google Scholar
15. Nguyen, M., et al. 2002. Receptors and signaling mechanisms required for prostaglandin E2-mediated regulation of mast cell degranulation and IL-6 production. J. Immunol. 169:4586-4593.
    View this article via: PubMed Google Scholar
16. Tilley, S.L., et al. 2003. Identification of A3 receptor- and mast cell-dependent and -independent components of adenosine-mediated airway responsiveness in mice. J. Immunol. 171:331-337.
    View this article via: PubMed Google Scholar
17. Juillerat, L., et al. 1990. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension. 16:564-572.
    View this article via: PubMed Google Scholar
18. Urata, H., Kinoshita, A., Misono, K.S., Bumpus, F.M., Husain, A. 1990. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J. Biol. Chem. 265:22348-22357.
    View this article via: PubMed Google Scholar
19. Jenne, D.E., Tschopp, J. 1991. Angiotensin II-forming heart chymase is a mast-cell-specific enzyme. Biochem. J. 276:567-568.
    View this article via: PubMed Google Scholar
20. Nataraj, C., et al. 1999. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J. Clin. Invest. 104:1693-1701.
    View this article via: JCI PubMed Google Scholar
21. Theoharides, T.C., Cochrane, D.E. 2004. Critical role of mast cells in inflammatory diseases and the effect of acute stress. J. Neuroimmunol. 146:1-12.
    View this article via: PubMed Google Scholar
22. Constantinides, P. 1995. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction [editorial]. Circulation. 9:2:108. 3.
23. Kovanen, P.T., Kaartinen, M., Paavonen, T. 1995. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation. 92:1084-1088.
    View this article via: PubMed Google Scholar
24. Laine, P., et al. 1999. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation. 99:361-369.
    View this article via: PubMed Google Scholar
25. Hara, M., et al. 2002. Evidence for a role of mast cells in the evolution to congestive heart failure. J. Exp. Med. 195:375-381.
    View this article via: PubMed Google Scholar