Role of Mast Cells in Progressive Renal Diseases : Journal of the American Society of Nephrology

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Role of Mast Cells in Progressive Renal Diseases

Holdsworth, Stephen R.; Summers, Shaun A.

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Journal of the American Society of Nephrology 19(12):p 2254-2261, December 2008. | DOI: 10.1681/ASN.2008010015
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The mast cell, originally named “fattened or well-fed cell” (Mastzellen) by Ehrlich,1 is a sentinel for host defense.2 After recent discoveries demonstrated an expanded role for mast cells in both systemic and local host immune responses, Galli3 suggested the name “master” cell would be more appropriate. Mast cells are present in low numbers in all vascular organs, including the kidney. In chronic progressive kidney diseases, mast cell proliferation in tubulointerstitial injury is prominent regardless of the initiating disease and correlates with progressive loss of function and poor outcome.

Outside the kidney, mast cell biology is a rapidly advancing field. Mast cells have diverse functional capacities well beyond those associated with allergy and IgE. Rodents genetically deficient in mast cells have been extensively studied to determine whether these cells play a role in models of human disease, and, as it turns out, mast cells have functional roles in vivo in chronic diseases associated with inflammation and autoimmunity. Their participation in a diverse range of human kidney diseases is also now clear, and their phenotypic characterization; mechanism of recruitment and proliferation; and possible roles in inflammation, fibrosis, remodeling, and repair are now open to exploration. This review focuses on the biology of mast cells, mast cells in fibrosis, the renin-angiotensin system (RAS) in mast cell fibrosis, and the role of mast cells in autoimmune kidney diseases.


Mast cells derive from hematopoietic progenitor cells. They migrate through vascularized tissue to complete their maturation.4 Mast cells are tissue-specific multifunctional cells, with diverse phenotypes in different anatomic sites in various species, collectively referred to as “mast cell heterogeneity.”2,4 They locate close to blood vessels, epithelia, and nerves in connective tissues, allowing their participation in homeostatic functions as well as being strategic sentinels at primary immune barriers where their density is increased. Their anatomic distribution and structural relationships allow mast cells to modulate innate immune and adaptive effector responses; however, this role requires mast cell activation to stimulate cell degranulation together with synthetic molecule release.

The best known, classical pathway of mast cell activation is through IgE-Fcε cross-linking.5 The role mast cells serve in expulsion of parasites from their host is well known.2 More recent studies recognized additional, alternative, activating pathways including complement and signaling through microbial pattern recognition receptors, toll-like receptors (TLR). This work has expanded our understanding of a role for mast cells in host defense in other diseases.

In animal models of bacterial infection, including bacterial peritonitis, mast cells are required for optimal innate immune responses conferring survival benefit.6,7 Complement also activates mast cells, and complement-dependant microbial killing is at least partially dependent on mast cell function for full expression.8 The pattern recognition receptors, TLR, serve as an important link between innate and adaptive immunity. Both mouse9,10 and human mast cells11 express TLR. In animal models, the important synergistic interaction between TLR in mast cells demonstrates upregulated cytokine production12 and increased survival from bacterial infection.13 In addition to complement and TLR activation, stress hormones, in particular corticotrophin-releasing hormone, enhances mast cell activation and degranulation, facilitating further mediator release.14

As well as these novel pathways, several other molecules can initiate mast cell activation. These include growth factors such as stem cell factor, co-stimulatory molecules CD28 (and ligands CD80/86), the integrins, and CCR1.15 The close proximity of mast cells to neurons facilitates neuropeptide activation of mast cells.16 Mast cells are also important in chronic inflammation with the capacity to produce a range of bioactive amines, proteoglycans, growth hormones, chemokines, and cytokines, which mediate a diverse range of mast cell function (Figure 1). This breadth of activity has been reviewed extensively.2,17,18


Although mast cells are found infrequently in normal kidney tissue, their numbers increase significantly in the setting of renal disease. Mast cells are prominent in tubulointerstitial nephritis associated with progressive fibrosis and renal failure. These include almost all of the primary and secondary forms of glomerulonephritis,1930 diabetic nephropathy,31,32 and allograft rejection,3338 as well as amyloid,39 renovascular ischemia,40 reflux nephropathy,41 polycystic kidney disease,42 and drug-induced nephropathy.19 Mast cell presence is correlated semiquantitatively with fibrosis, progressive decline in glomerular filtration, and poor outcome.2022,24,25,27,29 The intensity and extent of tubulointerstitial damage is one of the strongest determinants of progressive functional decline.43,44

Interstitial inflammation and fibrosis involve a common sequence of events requiring the interaction of tubular and interstitial cells with infiltrating leukocytes. Early events in this process involve leukocyte (including mast cell) recruitment and epithelial-mesenchymal transition forming fibroblasts. Profibrotic stimuli include key growth factors, TGF-β45 and fibroblast growth factor, as well as inflammatory cytokines and chemokines facilitating leukocyte recruitment and activation. Tubular epithelial cells play an important role in these processes, and the release of proteolytic enzymes, including matrix metalloproteases (MMP), mediates fibrogenic injury. The balance of overall activators and inhibitors is altered in a manner favoring net matrix deposition and scarification.

Mast cells have the potential to support this process actively. They elaborate cytokines,46 chemokines,47 and leukotrienes48 recruiting and activating leukocytes. They also indirectly support leukocyte recruitment by affecting vascular endothelial expression of selectins and adhesion molecules.49,50 Mast cell degranulation leads to the release of histamine, heparin, and cytokines, in particular IL-451 and TNF-α,52 which can influence fibroblast function. Furthermore, the release of TGF-β,53 MMP-9,54 and a variety of proteases, principally tryptase and chymase, contributes to progressive fibrogenesis.55,56 In addition to direct injury, some proteases are capable of activating latent MMP and other proteases. They also serve as chemoattractants and mitogens for fibroblasts. Growth factors are mediators of mast cell–associated histologic and functional kidney injury,57 although their mechanism of action is complex.


Current understanding of the systemic RAS suggests it is rate limited by renin release from juxtaglomerular cells in response to renal baroreceptors or sodium chloride delivery to the macula densa.58 There is growing interest in the local role of the RAS in specific tissues.

The kidney provides all of the necessary molecular components for a functional RAS, and there is increasing evidence of the participation of the intrarenal RAS in the pathophysiology of chronic renal injury.59 RAS activity predictably plays a profibrotic role in chronic renal disease. Angiotensin II (AngII) stimulates TGF-β production60 and suppresses matrix degradation,61 favoring increased extracellular matrix deposition.62 Mounting evidence supports the role of the local RAS through AngII in regulating cell proliferation, apoptosis, and fibrosis.63,64

There is immunohistochemical evidence of increased expression of the local RAS in human proliferative glomerulonephritis65,66 and experimental evidence to support a functional role in injury through AT1 receptors in anti–glomerular basement membrane (anti-GBM) disease.67 In anti–Thy-1 antibody–induced glomerulonephritis, infusion of AngII receptor blocker attenuates injury and reduces matrix expansion and sclerosis.68 In diabetic nephropathy, there also is evidence of renal RAS activation, as gene activation of angiotensin converting enzyme (ACE) is enhanced despite normal to low renin expression.69 Blockade of the RAS reduces the rate of progression of renal dysfunction in both type 1 and type 2 diabetes.70,71 Furthermore, AngII induces TGF-β in diabetic nephropathy.72 ACE inhibition in human type 2 diabetic nephropathy reduces renal TGF-β gene expression.73

The possible relevance of the close association among interstitial fibrosis, mast cell accumulation, and the role of the local renal RAS is highlighted by recent studies showing that mast cells induce RAS activation. Mast cells also synthesize renin.74 Renin released during mast cell degranulation also generates AngI.75 Cardiac mast cell–derived renin is pathologically important in models of ischemia-induced cardiac arrhythmias.75 Renin overflow and arrhythmias in cardiac ischemia/reperfusion injury both were significantly reduced in mast cell–deficient mice and in normal mice given mast cell stabilizers. In the heart, as in the kidney, mast cell infiltration is seen in most forms of chronic injury, including coronary atherosclerosis and cardiomyopathies.76

It has been known for some time that there are alternative pathways for converting AngI to AngII that do not require ACE. This has provided support for the argument that therapeutic combinations of angiotensin receptor blockers (ARB) and ACE inhibitors are theoretically superior to ACE inhibitors alone in blocking local RAS. One alternative AngII-generating pathway is through the enzyme chymase. This is a major pathway for AngII generation in renal artery clipping–induced hypertension.77 Furthermore, chymase inhibitors prevented AngII and TGF-β generation in a model of cardiac failure.78 Mast cells are the major tissue source of chymase.79

Huang et al.80 demonstrated marked upregulation of chymase in human diabetic nephropathy where ACE was also upregulated. Whereas no difference in ACE expression was seen in normal versus hypertensive patients, chymase expression was significantly higher in patients with hypertension, suggesting that chymase may be an important therapeutic target in addition to ACE.80 The importance of chymase is also confirmed by studies in polycystic kidney disease, where mast cells are associated with tubulointerstitial damage. Strong AngII-generating capacity, as a result of chymase, was found in 13 of 14 patients with polycystic disease, and mast cells were found to be the source of chymase.42

In streptozotocin-induced diabetes, fibrosis in mesenteric vessel is associated with mast cell infiltration. Mast cells stain for chymase, TGF-β, and tryptase. Administration of a mast cell stabilizer reduces fibrosis and the number of chymase-positive mast cells, without affecting TGF-β expression, consistent with a role for fibrosis-induced by chymase-generated AngII.31 A further link between AngII and mast cells comes from a rodent study of fibrosis after five-sixths nephrectomy. TGF-β staining, chymase-positive mast cells infiltrate areas of fibrosis in association with increased expression of stem cell factor and IL-8, known mast cell attractants. This fibrosis was prevented by treatment with ACE inhibitors, suggesting a feedback link between AngII-induced mast cell chemoattractants and ACE-independent generation of AngII by mast cells.81 These studies collectively provide evidence for mast cell–induced renal fibrosis by newly discovered pathways leading to mast cell activation of local RAS.


Mast cells have been associated with fibrosis in other organs besides the kidney, including skin,82 experimental models of lung fibrosis,83 and scleroderma.84 The availability of mast cell–deficient and mast cell–“knock-in” (bone marrow reconstituted) mice confirm a role for mast cells in some forms of tissue fibrosis in vivo. The models include homocysteine-induced cardiac remodeling85 and pancreatic fibrosis,86 where the unexpected outcomes suggest mast cells protect against the development of fibrosis. In several other models, including bleomycin-induced pulmonary fibrosis,87,88 carbon tetrachloride–induced liver fibrosis,89 and murine scleroderma,90 mast cell–deficient mice showed no reduction in fibrosis.

Models of renal injury producing fibrosis in mast cell–deficient mice have not been as extensively studied, but preliminary data do not show a functional role for mast cells in this fibrogenesis. In puromycin aminonucleoside–induced nephrosis, mast cell–deficient mice had enhanced fibrosis. These KitW-sh/KitW-sh null mice surprisingly had increased levels of mRNA encoding TGF-β, suggesting an unexpected role for mast cells in modulating TGF-β expression in this model. In vitro experiments showed that heparin inhibited the expression of mRNA encoding TGF-β in cultured rat fibroblasts.91 Preliminary studies in a murine model of ureteral obstruction also suggested that mast cells protect against fibrosis.92 Thus, data from experimental mast cell–deficient mice do not support the attractive hypothesis that mast cells play a profibrotic role in chronic renal disease. In fact, the data suggest that the net outcome of mast cell involvement is either mitigation of fibrosis or facilitation of repair.


The central role of mast cells in asthma, allergy, hypersensitivity, and anaphylactic reactions has been extensively studied and recently reviewed.9395 As outlined already, mast cells now feature much broader roles in immunity and inflammation. The predominant sense surrounding mast cells in these settings is they facilitate, among other facilitators, the development of immune responses and inflammation at multiple levels, and this inflammation can be fibrogenic. There are data, albeit more limited, that suggest that mast cells can also act as modulators of inflammation.

In addition to their role in host defense through activation of the innate immune system, mast cells confer resistance to endogenous and exogenous toxins and venoms by interactions with adaptive immunity through IgE-Fcε receptors.96 Exaggerated IgE/mast cell responses are widely known to cause anaphylactic and allergic disease.97 These latter responses have limited relevance to kidney injury except for some drug-induced nephropathies.

Mast cells also have close adjacencies to T cells in secondary lymphoid organs and in the periphery.98 They present antigens to naive T cells in an MHC-restricted manner.99,100 Mast cells stimulate the migration of antigen-presenting cells to nodes through the release of IL-1, -3, and -6 and TNF.101 They also influence T cell differentiation: IL-4 and histamine direct Th2 responses102 as well as modulate the differentiation of Th17+ CD4 cells.103 It is in the generation of effector responses, however, where mast cells may have the greatest impact. Mast cells in the periphery enhance effector T cell recruitment directly by the production of chemoattractants. LTB4 from mast cells recruits CD8 cells,104 and IL-16 recruits CD4 cells.46 Mast cells also recruit effector T cells indirectly by their cytokine activation of local vascular endothelia enhancing the expression of intercellular adhesion molecule 1 and vascular cellular adhesion molecule, leukocyte adherence, and transmigration.105 T cell/mast cell activation is also bidirectional. T cell cytokines activate mast cells106 and enhance their proliferation through IL-3.107

Mast cells also have the potential to act as immunoregulators of adaptive immunity because of their potential to produce TGF-β, IL-4 and -10, and histamine. There have been only limited examples of this in vivo induction of contact hypersensitivity by ultraviolet irradiation leading to mast cell histamine release in vivo.108 Recent work on transplant tolerance (mediated by local graft T regulatory cells) showed a new role for mast cells as immune modulators. Transplanted skin allografts into class II mismatched (KitW-sh/KitW-sh) mast cell–deficient recipients were rejected but this did not happen in mast cell–reconstituted recipients. Other evidence suggests that T regulatory cells recruit mast cells by their production of IL-9.109 IL-9 is a cytokine that enhances mast cell growth and functionality.110

Mast cell–deficient mice have been used in a number of animal models of human autoimmune disease. They include experimental allergic encephalomyelitis,111 delayed-type hypersensitivity (DTH),112 the Arthus response,113 Bullous pemphigoid,114 experimental vasculitis,115 atherosclerosis,116 antigen-induced arthritis,117 anti-GPI antibody–induced arthritis in KBxN mice,118 and dermal contact hypersensitivity.119 These studies provide increasing evidence for a functional role of mast cells in disease.

The mechanisms of facilitation by mast cells in these models are variable and speculative in some. In models induced by antibody (pemphigoid, K/BxN arthritis), complement anaphylatoxins and FcR cross-linking are likely mast cell activators. The resulting mast cell activation enhances pathologic immunity. Most of the other models are dependant on T cell–directed immune responses. As discussed, the bidirectional T cell–mast cell interaction supporting the development of T cell responses is the likely explanation for the injurious role of mast cells in these models. In some of these T cell models, mast cell IgE-Fcε linking may also be necessary to prime mast cells for subsequent T cell activation and injury.120,121 Mast cell priming by IgE is necessary to facilitate T effector cell responses causing contact hypersensitivity.120 Interestingly, such priming occurs with antigen-independent IgE.

A number of studies have also analyzed the facilitative injury of mast cells in anti-GBM nephritis. Timoshanko et al.122 demonstrated a role for mast cells in inducing functional renal injury by the mechanism of infiltrating mast cells that recruit DTH effector leukocytes. These local effects were comparable to studies showing a role for mast cells in dermal DTH.112 Two other studies demonstrated a potential protective role for mast cells in this model. This was not attributable to local effects, because mast cells were not visible in renal sections. With the association of mast cells and T regulatory cells already established,109 one study suggested that systemic mast cells infiltrate local lymphoid organs and activate regulatory T cells to confer protection.123 Kanamaru et al.124 attributed the beneficial outcome of mast cell–competent mice to improved repair function in the kidney. In a model of autoimmune immune complex disease, the absence of mast cells facilitated an altered pattern of disease but did not alter the severity of injury.125 A recent study using anti-GBM nephritis in rats showed that histamine and histamine agonists can significantly attenuate renal inflammation. In this Th1-driven, DTH-mediated model, histamine reduced the expression of the Th1-inducing cytokine IL-12.126


There is a role for mast cells in immune homeostasis beyond simple allergy. Mast cells participate in many inflammatory kidney diseases, particularly those associated with fibrosis. Mast cells have very diverse roles ranging from proinflammatory to immunomodulatory. Currently, the mechanisms determining the specific, functional phenotype of involvement are not fully understood. Mast cells also have the potential to induce injury and fibrosis, possibly by mast cell activation of the local RAS; however, current evidence, although insufficient to draw firm conclusions, does not support a functional role for mast cells in renal fibrosis. Studies in experimental inflammatory renal disease are also limited but show diverse, active roles for mast cells, ranging from protection from disease to enhancement. Further work is required to determine which factors drive their pathologic participation. Other approaches are also needed to identify potential therapeutic targets as well as define potential protective regulatory pathways induced by mast cells.



Figure 1:
Mediator release and physiologic responses to mast cell degranulation. Mast cell degranulation results in the release of preformed mediators and the release of others that are responsible for their diverse physiologic effects. These mediators include growth factors, proteases, leukotrienes, cytokines, and chemokines. Release of these mediators facilitates the actions of mast cells ranging from enhanced vascular permeability and leukocyte recruitment to fibrosis and immunomodulation.

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1. Ehrlich P: Contributions to the theory and practice of histological staining [Doctoral thesis], Leipzig, Germany, University of Leipzig, 1878
2. Marshall JS: Mast-cell responses to pathogens. Nat Rev Immunol 4: 787–799, 2004
3. Galli SJ: New concepts about the mast cell. N Engl J Med 328: 257–265, 1993
4. Kitamura Y: Heterogeneity of mast cells and phenotypic change between subpopulations. Annu Rev Immunol 7: 59–76, 1989
5. Beaven MA, Metzger H: Signal transduction by Fc receptors: The Fc epsilon RI case. Immunol Today 14: 222–226, 1993
6. Echtenacher B, Mannel DN, Hultner L: Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381: 75–77, 1996
7. Malaviya R, Ikeda T, Ross E, Abraham SN: Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature 381: 77–80, 1996
8. Prodeus AP, Zhou X, Maurer M, Galli SJ, Carroll MC: Impaired mast cell-dependent natural immunity in complement C3-deficient mice. Nature 390: 172–175, 1997
9. McCurdy JD, Lin TJ, Marshall JS: Toll-like receptor 4-mediated activation of murine mast cells. J Leukoc Biol 70: 977–984, 2001
10. Supajatura V, Ushio H, Nakao A, Akira S, Okumura K, Ra C, Ogawa H: Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest 109: 1351–1359, 2002
11. Okumura S, Kashiwakura J, Tomita H, Matsumoto K, Nakajima T, Saito H, Okayama Y: Identification of specific gene expression profiles in human mast cells mediated by Toll-like receptor 4 and FcepsilonRI. Blood 102: 2547–2554, 2003
12. Qiao H, Andrade MV, Lisboa FA, Morgan K, Beaven MA: FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107: 610–618, 2006
13. Supajatura V, Ushio H, Nakao A, Okumura K, Ra C, Ogawa H: Protective roles of mast cells against enterobacterial infection are mediated by Toll-like receptor 4. J Immunol 167: 2250–2256, 2001
14. Christy AL, Brown MA: The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J Immunol 179: 2673–2679, 2007
15. Bachelet I, Levi-Schaffer F: Mast cells as effector cells: A co-stimulating question. Trends Immunol 28: 360–365, 2007
16. Slominski AT: Proopiomelanocortin signaling system is operating in mast cells. J Invest Dermatol 126: 1934–1936, 2006
17. Dawicki W, Marshall JS: New and emerging roles for mast cells in host defence. Curr Opin Immunol 19: 31–38, 2007
18. Bischoff SC: Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nat Rev Immunol 7: 93–104, 2007
19. Roberts IS, Brenchley PE: Mast cells: The forgotten cells of renal fibrosis. J Clin Pathol 53: 858–862, 2000
20. Otsubo S, Nitta K, Uchida K, Yumura W, Nihei H: Mast cells and tubulointerstitial fibrosis in patients with ANCA-associated glomerulonephritis. Clin Exp Nephrol 7: 41–47, 2003
21. Kondo S, Kagami S, Kido H, Strutz F, Muller GA, Kuroda Y: Role of mast cell tryptase in renal interstitial fibrosis. J Am Soc Nephrol 12: 1668–1676, 2001
    22. El-Koraie AF, Baddour NM, Adam AG, El Kashef EH, El Nahas AM: Role of stem cell factor and mast cells in the progression of chronic glomerulonephritides. Kidney Int 60: 167–172, 2001
    23. Ehara T, Shigematsu H: Contribution of mast cells to the tubulointerstitial lesions in IgA nephritis. Kidney Int 54: 1675–1683, 1998
      24. Toth T, Toth-Jakatics R, Jimi S, Ihara M, Urata H, Takebayashi S: Mast cells in rapidly progressive glomerulonephritis. J Am Soc Nephrol 10: 1498–1505, 1999
      25. Hiromura K, Kurosawa M, Yano S, Naruse T: Tubulointerstitial mast cell infiltration in glomerulonephritis. Am J Kidney Dis 32: 593–599, 1998
      26. Ravinal RC, Costa RS, Coimbra TM, Dantas M, dos Reis MA: Mast cells, TGF-beta1 and myofibroblasts expression in lupus nephritis outcome. Lupus 14: 814–821, 2005
        27. Zhang GP, Dang XQ, Yi ZW, He XJ, Zhang JJ, Wu XC, Mo SH: Role of mast cells in the development of renal interstitial fibrosis in children with Henoch-Schonlein purpura nephritis [in Chinese]. Zhongguo Dang Dai Er Ke Za Zhi 9: 125–128, 2007
        28. El Kossi MM, El Nahas AM: Stem cell factor and crescentic glomerulonephritis. Am J Kidney Dis 41: 785–795, 2003
          29. Kurusu A, Suzuki Y, Horikoshi S, Shirato I, Tomino Y: Relationship between mast cells in the tubulointerstitium and prognosis of patients with IgA nephropathy. Nephron 89: 391–397, 2001
          30. Danilewicz M, Wagrowska-Danilewicz M: Quantitative analysis of the interstitial mast cells in idiopathic mesangiocapillary glomerulonephritis type I. Nefrologia 21: 253–259, 2001
          31. Jones SE, Gilbert RE, Kelly DJ: Tranilast reduces mesenteric vascular collagen deposition and chymase-positive mast cells in experimental diabetes. J Diabetes Complications 18: 309–315, 2004
          32. Ruger BM, Hasan Q, Greenhill NS, Davis PF, Dunbar PR, Neale TJ: Mast cells and type VIII collagen in human diabetic nephropathy. Diabetologia 39: 1215–1222, 1996
          33. Ishida T, Hyodo Y, Ishimura T, Takeda M, Hara I, Fujisawa M: Mast cell numbers and protease expression patterns in biopsy specimens following renal transplantation from living-related donors predict long-term graft function. Clin Transplant 19: 817–824, 2005
          34. Pardo J, Diaz L, Errasti P, Idoate M, de Alava E, Sola I, Lozano L, Panizo A: Mast cells in chronic rejection of human renal allografts. Virchows Arch 437: 167–172, 2000
            35. Lajoie G, Nadasdy T, Laszik Z, Blick KE, Silva FG: Mast cells in acute cellular rejection of human renal allografts. Mod Pathol 9: 1118–1125, 1996
              36. Abo-Zenah H, Katsoudas S, Wild G, de Takats D, Shortland J, Brown CB, El Nahas AM: Early human renal allograft fibrosis: cellular mediators. Nephron 91: 112–129, 2002
                37. Colvin RB, Dvorak HF: Letter: Basophils and mast cells in renal allograft rejection. Lancet 1: 212–214, 1974
                  38. Yamada M, Ueda M, Naruko T, Tanabe S, Han YS, Ikura Y, Ogami M, Takai S, Miyazaki M: Mast cell chymase expression and mast cell phenotypes in human rejected kidneys. Kidney Int 59: 1374–1381, 2001
                  39. Danilewicz M, Wagrowska-Danilewicz M: Quantitative analysis of interstitial mast cells in AA and AL renal amyloidosis. Pathol Res Pract 198: 413–419, 2002
                  40. Morikawa T, Imanishi M, Suzuki H, Okada N, Okumura M, Konishi Y, Yoshioka K, Takai S, Miyazaki M: Mast cell chymase in the ischemic kidney of severe unilateral renovascular hypertension. Am J Kidney Dis 45: e45–e50, 2005
                  41. Solari V, Unemoto K, Piaseczna Piotrowska A, Puri P: Increased expression of mast cells in reflux nephropathy. Pediatr Nephrol 19: 157–163, 2004
                  42. McPherson EA, Luo Z, Brown RA, LeBard LS, Corless CC, Speth RC, Bagby SP: Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease. J Am Soc Nephrol 15: 493–500, 2004
                  43. Austin HA 3rd, Boumpas DT, Vaughan EM, Balow JE: Predicting renal outcomes in severe lupus nephritis: Contributions of clinical and histologic data. Kidney Int 45: 544–550, 1994
                  44. Bohle A, Mackensen-Haen S, von Gise H: Significance of tubulointerstitial changes in the renal cortex for the excretory function and concentration ability of the kidney: A morphometric contribution. Am J Nephrol 7: 421–433, 1987
                  45. Border WA, Noble NA: Transforming growth factor beta in tissue fibrosis. N Engl J Med 331: 1286–1292, 1994
                  46. Rumsaeng V, Cruikshank WW, Foster B, Prussin C, Kirshenbaum AS, Davis TA, Kornfeld H, Center DM, Metcalfe DD: Human mast cells produce the CD4+ T lymphocyte chemoattractant factor, IL-16. J Immunol 159: 2904–2910, 1997
                  47. Selvan RS, Butterfield JH, Krangel MS: Expression of multiple chemokine genes by a human mast cell leukemia. J Biol Chem 269: 13893–13898, 1994
                  48. Ott VL, Cambier JC, Kappler J, Marrack P, Swanson BJ: Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat Immunol 4: 974–981, 2003
                  49. Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF: Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci U S A 88: 4220–4224, 1991
                  50. Meng H, Marchese MJ, Garlick JA, Jelaska A, Korn JH, Gailit J, Clark RA, Gruber BL: Mast cells induce T-cell adhesion to human fibroblasts by regulating intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. J Invest Dermatol 105: 789–796, 1995
                  51. Trautmann A, Krohne G, Brocker EB, Klein CE: Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4. J Immunol 160: 5053–5057, 1998
                  52. Gibbs BF, Wierecky J, Welker P, Henz BM, Wolff HH, Grabbe J: Human skin mast cells rapidly release preformed and newly generated TNF-alpha and IL-8 following stimulation with anti-IgE and other secretagogues. Exp Dermatol 10: 312–320, 2001
                  53. Qu Z, Liebler JM, Powers MR, Galey T, Ahmadi P, Huang XN, Ansel JC, Butterfield JH, Planck SR, Rosenbaum JT: Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am J Pathol 147: 564–573, 1995
                  54. Baram D, Vaday GG, Salamon P, Drucker I, Hershkoviz R, Mekori YA: Human mast cells release metalloproteinase-9 on contact with activated T cells: Juxtacrine regulation by TNF-alpha. J Immunol 167: 4008–4016, 2001
                  55. Cairns JA, Walls AF: Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest 99: 1313–1321, 1997
                  56. Gruber BL, Kew RR, Jelaska A, Marchese MJ, Garlick J, Ren S, Schwartz LB, Korn JH: Human mast cells activate fibroblasts: tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis. J Immunol 158: 2310–2317, 1997
                  57. Blank U, Essig M, Scandiuzzi L, Benhamou M, Kanamaru Y: Mast cells and inflammatory kidney disease. Immunol Rev 217: 79–95, 2007
                  58. Peters H, Unger T: Mast cells and the power of local RAS activation. Nephrol Dial Transplant 22: 40–42, 2007
                  59. Kobori H, Nangaku M, Navar LG, Nishiyama A: The intrarenal renin-angiotensin system: From physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59: 251–287, 2007
                  60. Kaneto H, Morrissey J, Klahr S: Increased expression of TGF-beta 1 mRNA in the obstructed kidney of rats with unilateral ureteral ligation. Kidney Int 44: 313–321, 1993
                  61. Kagami S, Kuhara T, Okada K, Kuroda Y, Border WA, Noble NA: Dual effects of angiotensin II on the plasminogen/plasmin system in rat mesangial cells. Kidney Int 51: 664–671, 1997
                  62. Border WA, Noble NA: Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension 31: 181–188, 1998
                  63. Wolf G, Neilson EG: Angiotensin II as a renal growth factor. J Am Soc Nephrol 3: 1531–1540, 1993
                  64. Mezzano SA, Ruiz-Ortega M, Egido J: Angiotensin II and renal fibrosis. Hypertension 38: 635–638, 2001
                  65. Miyake-Ogawa C, Miyazaki M, Abe K, Harada T, Ozono Y, Sakai H, Koji T, Kohno S: Tissue-specific expression of renin-angiotensin system components in IgA nephropathy. Am J Nephrol 25: 1–12, 2005
                  66. Chan LY, Leung JC, Tang SC, Choy CB, Lai KN: Tubular expression of angiotensin II receptors and their regulation in IgA nephropathy. J Am Soc Nephrol 16: 2306–2317, 2005
                  67. Hisada Y, Sugaya T, Yamanouchi M, Uchida H, Fujimura H, Sakurai H, Fukamizu A, Murakami K: Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice. J Clin Invest 103: 627–635, 1999
                  68. Mahmood J, Khan F, Okada S, Kumagai N, Morioka T, Oite T: Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis. Kidney Int 70: 1591–1598, 2006
                  69. Konoshita T, Wakahara S, Mizuno S, Motomura M, Aoyama C, Makino Y, Kawai Y, Kato N, Koni I, Miyamori I, Mabuchi H: Tissue gene expression of renin-angiotensin system in human type 2 diabetic nephropathy. Diabetes Care 29: 848–852, 2006
                  70. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329: 1456–1462, 1993
                  71. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–860, 2001
                  72. Border WA, Yamamoto T, Noble NA: Transforming growth factor beta in diabetic nephropathy. Diabetes Metab Rev 12: 309–339, 1996
                  73. Langham RG, Kelly DJ, Gow RM, Zhang Y, Cordonnier DJ, Pinel N, Zaoui P, Gilbert RE: Transforming growth factor-beta in human diabetic nephropathy: Effects of ACE inhibition. Diabetes Care 29: 2670–2675, 2006
                  74. Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R: Mast cells: A unique source of renin. Proc Natl Acad Sci U S A 101: 13607–13612, 2004
                  75. Mackins CJ, Kano S, Seyedi N, Schafer U, Reid AC, Machida T, Silver RB, Levi R: Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 116: 1063–1070, 2006
                  76. Reid AC, Silver RB, Levi R: Renin: At the heart of the mast cell. Immunol Rev 217: 123–140, 2007
                  77. Jin D, Takai S, Shiota N, Miyazaki M: Roles of vascular angiotensin converting enzyme and chymase in two-kidney, one clip hypertensive hamsters. J Hypertens 16: 657–664, 1998
                  78. Matsumoto T, Wada A, Tsutamoto T, Ohnishi M, Isono T, Kinoshita M: Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. Circulation 107: 2555–2558, 2003
                  79. Ihara M, Urata H, Kinoshita A, Suzumiya J, Sasaguri M, Kikuchi M, Ideishi M, Arakawa K: Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension 33: 1399–1405, 1999
                  80. Huang XR, Chen WY, Truong LD, Lan HY: Chymase is upregulated in diabetic nephropathy: Implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular disease. J Am Soc Nephrol 14: 1738–1747, 2003
                  81. Jones SE, Kelly DJ, Cox AJ, Zhang Y, Gow RM, Gilbert RE: Mast cell infiltration and chemokine expression in progressive renal disease. Kidney Int 64: 906–913, 2003
                  82. Kischer CW, Bunce H 3rd, Shetlah MR: Mast cell analyses in hypertrophic scars, hypertrophic scars treated with pressure and mature scars. J Invest Dermatol 70: 355–357, 1978
                  83. Suzuki N, Horiuchi T, Ohta K, Yamaguchi M, Ueda T, Takizawa H, Hirai K, Shiga J, Ito K, Miyamoto T: Mast cells are essential for the full development of silica-induced pulmonary inflammation: A study with mast cell-deficient mice. Am J Respir Cell Mol Biol 9: 475–483, 1993
                  84. Haynes DC, Gershwin ME: The immunopathology of progressive systemic sclerosis (PSS). Semin Arthritis Rheum 11: 331–351, 1982
                  85. Joseph J, Kennedy RH, Devi S, Wang J, Joseph L, Hauer-Jensen M: Protective role of mast cells in homocysteine-induced cardiac remodeling. Am J Physiol Heart Circ Physiol 288: H2541–H2545, 2005
                  86. Araki Y, Andoh A, Nakamura F, Tasaki K, Takenaka K, Komai Y, Doi H, Fujiyama Y, Bamba T: Mast cells may not play a crucial role in the pathogenesis of experimental closed duodenal loop-induced pancreatitis in rats. Pancreas 24: 298–302, 2002
                  87. Mori H, Kawada K, Zhang P, Uesugi Y, Sakamoto O, Koda A: Bleomycin-induced pulmonary fibrosis in genetically mast cell-deficient WBB6F1-W/Wv mice and mechanism of the suppressive effect of tranilast, an antiallergic drug inhibiting mediator release from mast cells, on fibrosis. Int Arch Allergy Appl Immunol 95: 195–201, 1991
                  88. Okazaki T, Hirota S, Xu ZD, Maeyama K, Nakama A, Kawano S, Hori M, Kitamura Y: Increase of mast cells in the liver and lung may be associated with but not a cause of fibrosis: Demonstration using mast cell-deficient Ws/Ws rats. Lab Invest 78: 1431–1438, 1998
                  89. Sugihara A, Tsujimura T, Fujita Y, Nakata Y, Terada N: Evaluation of role of mast cells in the development of liver fibrosis using mast cell-deficient rats and mice. J Hepatol 30: 859–867, 1999
                  90. Everett ET, Pablos JL, Harley RA, LeRoy EC, Norris JS: The role of mast cells in the development of skin fibrosis in tight-skin mutant mice. Comp Biochem Physiol A Physiol 110: 159–165, 1995
                  91. Miyazawa S, Hotta O, Doi N, Natori Y, Nishikawa K, Natori Y: Role of mast cells in the development of renal fibrosis: Use of mast cell-deficient rats. Kidney Int 65: 2228–2237, 2004
                  92. Lee A, Kim DH, Jung YJ, Kim W, Lee S, Park SK, Sung MJ, Kang KP: Protective effect of mast cells in a unilateral ureteral obstruction model [Abstract]. J Am Soc Nephrol 18: 181A, 2007
                  93. Finkelman FD: Anaphylaxis: Lessons from mouse models. J Allergy Clin Immunol 120: 506–515, quiz 516–517, 2007
                  94. Bloemen K, Verstraelen S, Van Den Heuvel R, Witters H, Nelissen I, Schoeters G: The allergic cascade: Review of the most important molecules in the asthmatic lung. Immunol Lett 113: 6–18, 2007
                    95. Pawankar R, Lee KH, Nonaka M, Takizawa R: Role of mast cells and basophils in chronic rhinosinusitis. Clin Allergy Immunol 20: 93–101, 2007
                    96. Metz M, Maurer M: Mast cells: Key effector cells in immune responses. Trends Immunol 28: 234–241, 2007
                    97. Williams CM, Galli SJ: The diverse potential effector and immunoregulatory roles of mast cells in allergic disease. J Allergy Clin Immunol 105: 847–859, 2000
                    98. Tanzola MB, Robbie-Ryan M, Gutekunst CA, Brown MA: Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course. J Immunol 171: 4385–4391, 2003
                    99. Frandji P, Oskeritzian C, Cacaraci F, Lapeyre J, Peronet R, David B, Guillet JG, Mecheri S: Antigen-dependent stimulation by bone marrow-derived mast cells of MHC class II-restricted T cell hybridoma. J Immunol 151: 6318–6328, 1993
                    100. Dimitriadou V, Mecheri S, Koutsilieris M, Fraser W, Al-Daccak R, Mourad W: Expression of functional major histocompatibility complex class II molecules on HMC-1 human mast cells. J Leukoc Biol 64: 791–799, 1998
                    101. Jawdat DM, Albert EJ, Rowden G, Haidl ID, Marshall JS: IgE-mediated mast cell activation induces Langerhans cell migration in vivo. J Immunol 173: 5275–5282, 2004
                    102. Jutel M, Watanabe T, Akdis M, Blaser K, Akdis CA: Immune regulation by histamine. Curr Opin Immunol 14: 735–740, 2002
                    103. Nakae S, Suto H, Berry GJ, Galli SJ: Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice. Blood 109: 3640–3648, 2007
                    104. Taube C, Miyahara N, Ott V, Swanson B, Takeda K, Loader J, Shultz LD, Tager AM, Luster AD, Dakhama A, Gelfand EW: The leukotriene B4 receptor (BLT1) is required for effector CD8+ T cell-mediated, mast cell-dependent airway hyperresponsiveness. J Immunol 176: 3157–3164, 2006
                    105. Meng H, Tonnesen MG, Marchese MJ, Clark RA, Bahou WF, Gruber BL: Mast cells are potent regulators of endothelial cell adhesion molecule ICAM-1 and VCAM-1 expression. J Cell Physiol 165: 40–53, 1995
                    106. Alam R, Kumar D, Anderson-Walters D, Forsythe PA: Macrophage inflammatory protein-1 alpha and monocyte chemoattractant peptide-1 elicit immediate and late cutaneous reactions and activate murine mast cells in vivo. J Immunol 152: 1298–1303, 1994
                    107. Lantz CS, Boesiger J, Song CH, Mach N, Kobayashi T, Mulligan RC, Nawa Y, Dranoff G, Galli SJ: Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 392: 90–93, 1998
                    108. Hart PH, Grimbaldeston MA, Swift GJ, Jaksic A, Noonan FP, Finlay-Jones JJ: Dermal mast cells determine susceptibility to ultraviolet B-induced systemic suppression of contact hypersensitivity responses in mice. J Exp Med 187: 2045–2053, 1998
                    109. Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J, Strom TB, Zheng XX, Noelle RJ: Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442: 997–1002, 2006
                    110. Zhou Y, McLane M, Levitt RC: Th2 cytokines and asthma: Interleukin-9 as a therapeutic target for asthma. Respir Res 2: 80–84, 2001
                    111. Secor VH, Secor WE, Gutekunst CA, Brown MA: Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J Exp Med 191: 813–822, 2000
                    112. Askenase PW, Van Loveren H, Kraeuter-Kops S, Ron Y, Meade R, Theoharides TC, Nordlund JJ, Scovern H, Gerhson MD, Ptak W: Defective elicitation of delayed-type hypersensitivity in W/Wv and SI/SId mast cell-deficient mice. J Immunol 131: 2687–2694, 1983
                    113. Sylvestre DL, Ravetch JV: A dominant role for mast cell Fc receptors in the Arthus reaction. Immunity 5: 387–390, 1996
                    114. Chen R, Ning G, Zhao ML, Fleming MG, Diaz LA, Werb Z, Liu Z: Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J Clin Invest 108: 1151–1158, 2001
                    115. Johnston B, Burns AR, Kubes P: A role for mast cells in the development of adjuvant-induced vasculitis and arthritis. Am J Pathol 152: 555–563, 1998
                    116. Sun J, Sukhova GK, Wolters PJ, Yang M, Kitamoto S, Libby P, MacFarlane LA, Mallen-St Clair J, Shi GP: Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med 13: 719–724, 2007
                    117. van den Broek MF, van den Berg WB, van de Putte LB: The role of mast cells in antigen induced arthritis in mice. J Rheumatol 15: 544–551, 1988
                    118. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB: Mast cells: A cellular link between autoantibodies and inflammatory arthritis. Science 297: 1689–1692, 2002
                    119. Villa I, Skokos D, Tkaczyk C, Peronet R, David B, Huerre M, Mecheri S: Capacity of mouse mast cells to prime T cells and to induce specific antibody responses in vivo. Immunology 102: 165–172, 2001
                    120. Bryce PJ, Miller ML, Miyajima I, Tsai M, Galli SJ, Oettgen HC: Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 20: 381–392, 2004
                    121. Brown MA, Tanzola MB, Robbie-Ryan M: Mechanisms underlying mast cell influence on EAE disease course. Mol Immunol 38: 1373–1378, 2002
                    122. Timoshanko JR, Kitching R, Semple TJ, Tipping PG, Holdsworth SR: A pathogenetic role for mast cells in experimental crescentic glomerulonephritis. J Am Soc Nephrol 17: 150–159, 2006
                    123. Hochegger K, Siebenhaar F, Vielhauer V, Heininger D, Mayadas TN, Mayer G, Maurer M, Rosenkranz AR: Role of mast cells in experimental anti-glomerular basement membrane glomerulonephritis. Eur J Immunol 35: 3074–3082, 2005
                    124. Kanamaru Y, Scandiuzzi L, Essig M, Brochetta C, Guerin-Marchand C, Tomino Y, Monteiro RC, Peuchmaur M, Blank U: Mast cell-mediated remodeling and fibrinolytic activity protect against fatal glomerulonephritis. J Immunol 176: 5607–5615, 2006
                    125. Lin L, Gerth AJ, Peng SL: Susceptibility of mast cell-deficient W/Wv mice to pristane-induced experimental lupus nephritis. Immunol Lett 91: 93–97, 2004
                    126. Tanda S, Mori Y, Kimura T, Sonomura K, Kusaba T, Kishimoto N, Kameyama H, Tamagaki K, Okigaki M, Hatta T, Sasaki S, Takeda K, Sado Y, Adachi N, Matsubara H: Histamine ameliorates anti-glomerular basement membrane antibody-induced glomerulonephritis in rats. Kidney Int 72: 608–613, 2007
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