International Journal of Molecular Sciences Review Mast Cell Chymase and Kidney Disease Shamila Vibhushan 1,2, Manuela Bratti 1,2 , Juan Eduardo Montero-Hernández 1,2 , Alaa El Ghoneimi 1,2,3, Marc Benhamou 1,2, Nicolas Charles 1,2 , Eric Daugas 1,2,4 and Ulrich Blank 1,2,* 1 Centre de Recherche sur l’inflammation, CNRS ERL8252, Faculté de Médecine site Bichat, Université de Paris, Inserm UMR1149, 16 rue Henri Huchard, F-75018 Paris, France; [email protected] (S.V.); [email protected] (M.B.); [email protected] (J.E.M.-H.); [email protected] (A.E.G.); [email protected] (M.B.); [email protected] (N.C.); [email protected] (E.D.) 2 Laboratoire d’Excellence Inflamex, Université de Paris, F-75018 Paris, France 3 Department of Pediatric Surgery and Urology, Hôpital Universitaire Robert Debré, Assistance Publique—Hôpitaux de Paris (APHP), F-75019 Paris, France 4 Service de Néphrologie, Groupe Hospitalier Universitaire Bichat-Claude Bernard, Assistance Publique—Hôpitaux de Paris (APHP), F-75019 Paris, France * Correspondence: [email protected] Abstract: A sizable part (~2%) of the human genome encodes for proteases. They are involved in many physiological processes, such as development, reproduction and inflammation, but also play a role in pathology. Mast cells (MC) contain a variety of MC specific proteases, the expression of which may differ between various MC subtypes. Amongst these proteases, chymase represents up to 25% of the total proteins in the MC and is released from cytoplasmic granules upon activation. Once secreted, it cleaves the targets in the local tissue environment, but may also act in lymph nodes infiltrated by MC, or systemically, when reaching the circulation during an inflammatory response. MC have been recognized as important components in the development of kidney disease. Based on this observation, MC chymase has gained interest following the discovery that it contributes to the angiotensin-converting enzyme’s independent generation of angiotensin II, an important Citation: Vibhushan, S.; Bratti, M.; inflammatory mediator in the development of kidney disease. Hence, progress regarding its role has Montero-Hernández, J.E.; El been made based on studies using inhibitors but also on mice deficient in MC protease 4 (mMCP-4), Ghoneimi, A.; Benhamou, M.; the functional murine counterpart of human chymase. In this review, we discuss the role and actions Charles, N.; Daugas, E.; Blank, U. of chymase in kidney disease. While initially believed to contribute to pathogenesis, the accumulated Mast Cell Chymase and Kidney data favor a more subtle view, indicating that chymase may also have beneficial actions. Disease. Int. J. Mol. Sci. 2021, 22, 302. https://doi.org/10.3390/ijms22010302 Keywords: kidney disease; angiotensin II; inflammation; mast cell; mast cell chymase Received: 8 December 2020 Accepted: 27 December 2020 Published: 30 December 2020 1. Introduction Publisher’s Note: MDPI stays neu- Chymase is a highly abundant mast-cell (MC) specific serine protease that is synthe- tral with regard to jurisdictional clai- sized as a pro-peptidase and activated by dipeptidyl peptidase I (also known as cathepsin ms in published maps and institutio- C) before being stored in a releasable form bound to highly negatively charged proteogly- nal affiliations. cans in MC cytoplasmic granules [1]. While human MCs have only one chymase (encoded by CMA1), mice express several chymases, including murine MC protease 1 (mMCP-1), mMCP-2, mMCP-4, mMCP-5 and mMCP-9, in different MC types. Although not the enzyme with the highest sequence homology to human α-chymase, mMCP-4, a β-chymase, Copyright: © 2020 by the authors. Li- most likely reflects its functional counterpart exhibiting a similar tissue distribution in censee MDPI, Basel, Switzerland. connective tissue-type MC and similar chymotryptic cleavage properties [2–4]. Human This article is an open access article chymase, as well as mMCP-4 and -5, are negatively charged and stored in MC granules in distributed under the terms and con- a complex with granular proteoglycans. By contrast, storage of the less negatively charged ditions of the Creative Commons At- tribution (CC BY) license (https:// mMCP-1 is proteoglycan-independent, with an intermediate phenotype being observed creativecommons.org/licenses/by/ for mMCP-2 [5]. When MC degranulate, proteoglycan-bound chymase is dispersed into 4.0/). the interstitial spaces that remain associated to proteoglycans, which protects it from its Int. J. Mol. Sci. 2021, 22, 302. https://doi.org/10.3390/ijms22010302 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 302 2 of 14 natural inhibitors (such as α1-antitrypsin, α2-antichymotrypsin, α-macroglobulin). Pro- teoglycan binding also limits its diffusion, allowing the enzyme to remain locally active in the long-term after release [6]. However, contrary to the notion that chymase acts only locally [3,7], new studies suggest that chymase also has systemic functions under inflammatory conditions [8–10]. Human chymase cleaves peptides after aromatic amino acids (Phe, Tyr, Trp and some- times Leu) in a variety of both endogenous and exogenous peptides and protein targets, albeit not all of them have been confirmed in vivo [4,11]. Some of these targets could also play a role in renal inflammatory diseases. In particular, human as well as some rodents’ chymases have been known for long to play a role in the generation of Angiotensin II (Ang II) from the Angiotensin I precursor [12–14] in tissues, including in the kidney. Thus, chymase may generate Ang II independently from the angiotensin-converting enzyme (ACE), one of the central enzymes of the classical renin-angiotensin system (RAS), which is an important regulator of intrarenal hemodynamics, glomerular filtration, as well as fluid and electrolyte homeostasis [15]. This generation of Ang II by chymase in the kid- neys was proposed as an important compensatory mechanism to maintain a steady-state Ang II formation in ACE knockout mice [16]. Another protease released by MCs, MC carboxypeptidase A (CPA), may play an additional role in the generation of Ang II and some antagonistic peptides [17]. Evidence based on the use of chymase inhibitors, or on studies in MC-deficient mice, clearly confirm that blood pressure regulation can also involve an ACE-independent intrarenal system of Ang II generation [18–20]. In addition to its Ang II generating activity, chymase was also shown to activate a number of pro- peptides involved in the inflammatory and tissue remodeling response, such as the latent transforming growth factor-β (TGF-β)[21,22], IL-33 [23], pro-matrix metalloproteinases (MMP) [24,25] and big endothelin 1 (the precursor of endothelin 1) [26,27]. There is also substantial evidence for its implication in the coagulation system, as it is capable to degrade thrombin and plasmin [28–30]. It also degrades proteins of the extracellular matrix, such as fibronectin [30,31], and a variety of other inflammatory proteins, including a select set of cytokines and adhesion receptors [10,11,32]. Kidney disease (KD) is a growing health problem worldwide with little treatment options so far, except for replacement therapy [33]. Although some forms of the disease are of genetic origin (i.e., polycystic KD), KD is generally initiated by an inflammatory process that starts with an injury that can be of toxic, metabolic (diabetes), hemodynamic (hyper-, hypo-tension), post-ischemic, infectious, autoimmune ... origin, affecting the kidney parenchyma, and particularly the glomeruli, renal vessels or tubulo-interstitial compartment (Figure1). The initial injury launches an inflammatory cascade which, in case of chronic stimulation or defective regulation, enters into a progressive phase, with the development of chronic KD (CKD) engendering the destruction of individual nephrons and blood vessels and finally end-stage renal failure (Figure1). The RAS system leading to the generation of Ang II has been recognized as a major factor of disease progression and renal fibrosis development. In medical care, the relentless decline in renal function can be slowed down by therapies that make use of ACE inhibitors or Ang II receptor type-1 antagonists [34,35]. The inflammatory response in kidney disease both during the acute and progressive phase is characterized by an interstitial infiltrate of leukocytes, which includes MCs [36–39]. The latter are localized predominantly in the interstitium, where they concentrate in areas close to tubules and blood vessels, but they never infiltrate glomeruli [39,40]. Int. J. Mol. Sci. 2021, 22, 302 3 of 14 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 15 FigureFigure 1. 1.Proposed Proposed functionsfunctions of chymase in in kidn kidneyey disease disease according according to to the the explicat explicationsions provided provided in inthe the text. text. The The red red scissors indicate enzymatic activity in KD, as demonstrated in scientific publications, while the grey scissors indicate pos- scissors indicate enzymatic activity in KD, as demonstrated in scientific publications, while the grey scissors indicate sible activities in KD. The green arrows indicate positive protective functions of chymase. The red arrows indicate disease- possibleaggravating activities functions in KD. of chymase. The green arrows indicate positive protective functions of chymase. The red arrows indicate disease-aggravating functions of chymase. 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