Chymase inhibition retards albuminuria in type 2 diabetes

Bivona, Benjamin J.; Seth, Dale M.; Satou, Ryousuke; Harrison‐Bernard, Lisa M.

doi:10.14814/phy2.14302

Cited by 10 publications

(7 citation statements)

References 50 publications

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“…Mast cells are also able to promote renal fibrosis via SCF/c-kit signaling pathway and induce tubular interstitial injury by increasing the production of proteases and inflammatory mediators, such as chymase, renin, TGF-β1 and TNF-α [70,71]. Inhibition or reduction of chymase-positive mast cells, ameliorated albuminuria in db/db mice [72]. A clinical trial with the chymase inhibitor BAY1142524 in patients with DN is now completed, but no results have been yet posted (NCT03412006).…”

Section: Mast Cellsmentioning

confidence: 99%

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Rayego‐Mateos

Morgado‐Pascual

Opazo-Ríos

et al. 2020

IJMS

187

127

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Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.

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Section: Mast Cellsmentioning

confidence: 99%

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Rayego‐Mateos

Morgado‐Pascual

Opazo-Ríos

et al. 2020

IJMS

187

127

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“…In a hamster type 1 diabetic model, myocardial fibrosis via the attenuation of angiotensin II concentration and oxidative stress in heart was attenuated by treatment with chymase inhibitors, TEI-F00806 and TEI-E00548 [ 88 ]. In a mouse type 2 diabetic model, a chymase inhibitor Suc-Val-Pro-Phe p (OPh) 2 reduced albuminuria and renal angiotensin II concentration [ 89 ]. In a streptozotocin-induced hamster diabetic model, a significant increase in blood glucose level was observed along with increases in chymase and angiotensin II-forming activities in pancreatic islets, and a chymase inhibitor attenuated the increases in blood glucose level [ 90 ].…”

Section: Role Of Chymase On Metabolic Syndrome Complicationsmentioning

confidence: 99%

Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

Jin

2020

IJMS

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The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a chymotrypsin-like enzyme produced in mast cells, has various enzymatic actions. These actions include activation of angiotensin II, matrix metalloproteinase (MMP)-9, and transforming growth factor (TGF)-β, which are associated with oxidative stress, inflammation, and fibrosis, respectively. Augmentation of chymase activity in the liver has been reported in various NASH models. Generation of hepatic angiotensin II and related oxidative stress is upregulated in NASH but attenuated by treatment with a chymase inhibitor. Additionally, increases in MMP-9 and accumulation of inflammatory cells are observed in NASH but are decreased by chymase inhibitor administration. TGF-β and collagen I upregulation in NASH is also attenuated by chymase inhibition. These results in experimental NASH models demonstrate that a chymase inhibitor can effectively ameliorate NASH via the reduction of oxidative stress, inflammation, and fibrosis. Thus, chymase may be a therapeutic target for amelioration of NASH.

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“…In support of a role for chymase in generating Ang II in the context of kidney pathology, pharmacological chymase inhibition was shown to suppress renal Ang II formation in diabetic mice [120] and in mice treated with Ang I (precursor of Ang II) [84]. Additionally, chymase inhibition has been shown to protect against albuminuria in diabetic mice [121] and rats [122], to protect against diabetes-induced oxidative stress and renal dysfunction in hamsters [123] and to confer pancreatic islet protection in experimental diabetes [124]. In line with a detrimental impact of chymase in kidney pathology, Mcpt4 was shown to partly account for the inflammation induced by partial ureteral obstruction [125].…”

Section: Chymase In Inflammatory Kidney Diseasementioning

confidence: 99%

Novel Insight into the in vivo Function of Mast Cell Chymase: Lessons from Knockouts and Inhibitors

Pejler

2020

J Innate Immun

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Mast cells are now recognized as key players in diverse pathologies, but the mechanisms by which they contribute in such settings are only partially understood. Mast cells are packed with secretory granules, and when they undergo degranulation in response to activation the contents of the granules are expelled to the extracellular milieu. Chymases, neutral serine proteases, are the major constituents of the mast cell granules and are hence released in large amounts upon mast cell activation. Following their release, chymases can cleave one or several of a myriad of potential substrates, and the cleavage of many of these could potentially have a profound impact on the respective pathology. Indeed, chymases have recently been implicated in several pathological contexts, in particular through studies using chymase inhibitors and by the use of chymase-deficient animals. In many cases, chymase has been shown to account for mast cell-dependent detrimental effects in the respective conditions and is therefore emerging as a promising drug target. On the other hand, chymase has been shown to have protective roles in other pathological settings. More unexpectedly, chymase has also been shown to control certain homeostatic processes. Here, these findings are reviewed.

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Chymase inhibition retards albuminuria in type 2 diabetes

Cited by 10 publications

References 50 publications

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

Novel Insight into the in vivo Function of Mast Cell Chymase: Lessons from Knockouts and Inhibitors

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