NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2007 22(1):40-42; doi:10.1093/ndt/gfl544
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Mast cells and the power of local RAS activation*
1Center for Cardiovascular Research, 2Department of Nephrology, 3Institute for Pharmacology and Toxicology, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany
Correspondence and offprint requests to: Harm Peters, MD, Department of Nephrology, Charité Universitätsmedizin Berlin, Charité, Campus Mitte, Humboldt University, Charitéplatz 1, D-10098 Berlin, Germany. Email: Harm.Peters{at}charite.de
Keywords: cardiac dysrhythmia; local RAS; mast cells; renin
More than 100 years ago, mast cells were discovered and named by Paul Ehrlich, who was the first to recognize this well-fed appearing cell loaded with huge cytoplasmic granules in various tissues [1]. Mast cells derive from CD34+ multipotent bone marrow progenitor cells which circulate in small numbers in the blood as basophilic leucocytes, and enter the mucosal surfaces and connective tissue compartments of multiple organs [2]. This distinct cell type is today best known for its key role in immunoglobulin-E-mediated allergic reactions such as bronchial asthma and anaphylactic reactions. More recently, however, mast cells have been found to be important modulators and mediators of innate immunity, chronic inflammation, tissue remodelling and organ fibrosis [3–5].
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Mast cell renin expression |
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Following up on novel non-immune functions of mast cells, a recent pioneering study by the group of Roberto Levi [6] from the Weill Medical College, Cornwall University, New York, provided compelling evidence that mast cells critically contribute to ventricular arrhythmias in myocardial ischaemia/reperfusion [6]. This group had previously documented that in normal hearts, mast cells are a rich extrarenal source of renin expression and release [7]. Renin, an aspartyl protease, is classically produced by the renal afferent arterioles. Its secretion into the circulation is tightly controlled via the juxtaglomerular apparatus by renal baroreceptors and the sodium chloride delivery to the macula densa in order to maintain body fluid volume and blood pressure homeostasis. Since angiotensinogen is present in excess in the blood stream and angiotensin-converting enzyme (ACE) is ubiquitously expressed in the vascular endothelium, renal release of renin is rate-limiting for activation of the systemic renin–angiotensin system (RAS). In addition to renin, it has lay been know for a long time that mast cells produce large amounts of chymase, an alternative enzymatic pathway to generate angiotensin II from angiotensin I [1]. Thus, mast cells by themselves bear the capacity to generate angiotensin II in local compartments from present angiotensinogen.
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Mast cell renin function |
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Having identified local renin expression in cardiac mast cells, Levi's group [6] then assessed the functional consequences of mast cell renin release in experimental cardiac ischaemia/reperfusion using ex vivo Langendorff mouse and guinea pig hearts. The group found that: (i) Stimulation of mast cell degranulation resulted in significant renin-mediated formation of angiotensin I in normal animal hearts. Subsequent local production of angiotensin II elicited norepinephrine release from cardiac sympathetic nerve terminals via the AT1 receptor (Figure 1); (ii) Experimental ischaemia/reperfusion showed a significant spill over of renin and norepinephrine in parallel to ventricular arrhythmias in guinea pig and mouse hearts; (iii) Both pharmacological mast cell stabilization and use of mast-cell-deficient mice markedly attenuated the chain of renin overflow, angiotensin II formation, nerve terminal norepinephrine release and ventricular arrhythmias. Comparable protection was achieved with specific renin and AT1 antagonism.
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The study by Levi et al. [6] is pioneering on two major issues: (i) Although the components of the renin–angiotensin system are locally expressed in various tissues, it has as yet been difficult to prove whether local RAS indeed may act autonomously. A proof of concept for the functional relevance of renin release outside the kidney has now been provided by Levi et al. [6]; (ii) Ventricular dysrhythmias following cardiac ischaemia/reperfusion have been thought to be of only cardiac cell origin. Levi's group now documents that mast cells, i.e. cells of the immune system, can be critical mediators of cardiac dysfunction as well. Accordingly, the study suggests that cardiac dysrhythmias following myocardial infarction may become preventable by mast cell pharmacological stabilization with drugs generally used to treat allergies and asthma.
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The power of mast cells |
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Mast cells contain a multitude of various secretory granules, indicating that their impact on physiology and pathophysiology is likely to go beyond just the local activation of RAS [1,4,5]. Upon stimulation, mast cells release a plethora of preformed and newly synthesized substances that are known to influence inflammation, organ function and remodelling, haemodynamics and tissue fibrosis. These substances include an array of proteases, vasoactive mediator, cytokines, chemokines and growth factors (overview in Table 1). How powerful and far-reaching mast cells can be is illustrated in cutaneous urticaria. In this clinical paradigm, a few dermal mast cells can trigger a dramatic change of large dermal surface areas.
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Mast cells in kidney disease |
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Reports on mast cells in renal disease are scattered [1,4,5]. Mast cell accumulation has been described in several immune kidney disorders such as IgA nephropathy, membranous nephropathy, crescentic glomerulonephritis and allograph rejection. In non-immune renal diseases, an increase in mast cell number has been reported in diabetic and hypertensive nephropathy [4,8].
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Renal mast cells may act profibrotic |
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Only a little is known about the function of mast cells in renal disease, but most information so far available points to a profibrotic role. A recent experimental study on non-immune hypertensive nephropathy provided strong indirect evidence for this [9]. In rats following 5/6-nephrectomy, mast cells were predominantly localized to regions of peritubular fibrosis and expressed the key fibrosis mediator transforming growth factor-ß1. In addition, interstitial mast cell accumulation was found to be reduced when the rats received renoprotective angiotensin II blockade. In line with these experimental findings is that in human IgA nephropathy and chronic allograft rejection, mast cells were predominately located in the renal interstitium and their number correlated positively with interstitial fibrosis and negatively with renal function [5]. On the other hand, interstitial fibrosis was not found to be attenuated in a strain of mast-cell-deficient rats with puromycin aminonucleoside nephrosis [10].
In conclusion, mast cells have been identified as a powerful source of local RAS activation in the heart. The occurrence of mast cells in primarily non-immune organ disorders, including the kidney, is intriguing and deserves clearly our future scientific attention.
Conflict of interest statement. None declared.
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Notes |
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*Basic science article this editorial is based on: Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release and arrhythmias in ischaemia/reperfusion. Mackins CJ, Kano S, Seyedi N et al. J Clin Invest 2006; 116: 1063–1070
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References |
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TopMast cell renin expressionMast cell renin functionThe power of mast...Mast cells in kidney...Renal mast cells may...References |
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- Ehara T and Shigematsu H. (2003) Mast cells in the kidney. Nephrology 8:130–138.[CrossRef][Medline]
- Metcalfe DD, Baram D, Mekori YA. (1997) Mast cells. Physiol Rev 77:1033–1079.
[Abstract/Free Full Text] - Puxeddu I, Piliponsky AM, Bachelet I, Levi Schaffer F. (2003) Mast cells in allergy and beyond. Int J Biochem Cell Biol 35:1601–1607.[CrossRef][ISI][Medline]
- Eddy AA. (2001) Mast cells find their way to the kidney. Kidney Int 60:375–377.[CrossRef][ISI][Medline]
- Rangan GK and Harris DC. (2003) A blast from the mast? Kidney Int 64:1134–1135.[CrossRef][ISI][Medline]
- Mackins CJ, Kano S, Seyedi N, 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.[CrossRef][ISI][Medline]
- Silver RB, Reid AC, Mackins CJ, et al. (2004) Mast cells: a unique source of renin. Proc Natl Acad Sci USA 101:13607–13612.
[Abstract/Free Full Text] - Welker P, Kramer S, Neumayer HH, et al. (2005) Mast cell infiltration in human hypertensive nephropathy (abstract). J Am Soc Nephrol 16:614A.
- Jones SE, Kelly DJ, Cox AJ, et al. (2003) Mast cell infiltration and chemokine expression in progressive renal disease. Kidney Int 64:906–913.[CrossRef][ISI][Medline]
- Miyazawa S, Hotta O, Doi N, et al. (2004) Role of mast cells in the development of renal fibrosis: use of mast cell-deficient rats. Kidney Int 65:2228–2237.[CrossRef][ISI][Medline]
Accepted in revised form: 14. 8.06
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