Impact of Mast Cell Chymase on Renal Disease Progression

Abstract

Chymase, a serine protease found in mast cell granules, is released into the interstitium following injury or inflammation. Chymase is the primary ACE-independent pathway of angiotensin II formation, and also functions to activate TGF-beta and other promoters of extracellular matrix degradation, thereby playing a role in tissue remodeling. In the diseased kidney, chymase-containing mast cells markedly increase and their density correlates with tubulointerstitial fibrosis severity. Studies in humans support the pathologic role of chymase in diabetic nephropathy, while animal studies form the basis for the importance of increased chymase-dependent angiotensin II formation in progressive hypertensive, diabetic and inflammatory nephropathies. Moreover, humans with kidney disease express chymase in diseased blood vessels in concordance with significantly elevated plasma chymase levels. Conversely, specific chymase inhibitors attenuate angiotensin II production and renal fibrosis in animal models, suggesting their potential therapeutic benefit in human nephropathy, where chymase-containing mast cells accumulate and contribute to progressive disease.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…However, alternative enzymes, such as cathepsins and chymases may produce functional AngII intracellularly (Kumar et al, 2008;Kumar and Boim, 2009). Depending on the cell type, cathepsin D can participate in the first step of intracellular AGT cleavage usually catalyzed by renin and the second step by chymase, not ACE (Wasse et al, 2012). Obviously, ACE inhibitors do not inhibit the intracellular RAS.…”

“…These are intricate, highly efficient endogenous pathways in cardiac and smooth muscle cells, renal tubular, mesenchymal, as well as inflammatory cells infiltrating various tissues. Contribution of alternative pathways involving chymases, tonins, neutral endopeptidases, and aminopeptidases can significantly vary relative to classic RAS in a pathologic setting (Carey and Siragy, 2003;Chua et al, 2010;Wasse et al, 2012;Naffah-Mazzacoratti et al, 2014;Su, 2014).…”

Original paper Renal interstitial mast cell count is significantly higher in membranoproliferative glomerulonephritis than in class IV lupus nephritis

“…Chymase has the ability to convert angiotensin I to angiotensin II, which regulates intrarenal blood flow, and also participates in renal interstitial fibrosis [11,12]. It is involved in renal remodeling by increasing the expression of transforming growth factor β (TGF-β) [13]. Tryptase is a serine protease expressed almost exclusively in mast cells.…”

Renal interstitial mast cell counts differ across classes of proliferative lupus nephritis

“…It has been shown that mast cells actively participate in interstitial inflammation and contribute to renal fibrosis [8][9][10].…”

“…In cases of inflammation or injury, chymase is released into the interstitium and by activating latent transforming growth factor-b (TGF-b), is implicated in tissue remodeling. The number of mast cells correlates with the severity of tubulointerstitial disease: chymase-positive mast cells correlate with the severity of interstitial fibrosis and intra-renal vascular resistance [9]. Mast cell tryptase may also be involved in the development of interstitial fibrosis [10].…”