Effects of the selective chymase inhibitor TEI‐F00806 on the intrarenal renin–angiotensin system in salt‐treated angiotensin I‐infused hypertensive mice

Abstract

The effects of the selective chymase inhibitor TEI-F00806 were examined on angiotensin I (Ang I)-induced hypertension and intrarenal angiotensin II (Ang II) production in salt-treated mice. Twelve-week-old C57BL male mice were given a high-salt diet (4% NaCl + saline (0.9% NaCl)), and divided into three groups: (1) sham + vehicle (5% acetic acid in saline), (2) Ang I (1 μg kg min , s.c.) + vehicle, and (3) Ang I + TEI-F00806 (100 mg kg day , p.o.) (n = 8-10 per group). Systolic blood pressure was measured weekly using a tail-cuff method. Kidney Ang II content was measured by radioimmunoassay. Chronic infusion of Ang I resulted in the development of hypertension (P < 0.001), and augmented intrarenal chymase gene expression (P < 0.05), angiotensinogen protein level (P < 0.001) and Ang II content (P < 0.01) in salt-treated mice. Treatment with TEI-F00806 attenuated the development of hypertension (P < 0.001) and decreased Ang II content of the kidney (P < 0.05), which was associated with reductions in renal cortical angiotensinogen protein levels (P < 0.001) and chymase mRNA expression (P < 0.05). These data suggest that a chymase inhibitor decreases intrarenal renin-angiotensin activity, thereby reducing salt-dependent hypertension.

Chymase Dependent Pathway of Angiotensin II Generation and Rapeseed Derived Peptides for Antihypertensive Treatment of Spontaneously Hypertensive Rats

“…It is speculated that chymase inhibition might become a new therapeutic strategy to treat some diseases, such as hypertension or diabetes (Wang et al, 2015;Ansary et al, 2018). This might be of particular importance when "ACE escape" phenomenon occurs after chronic treatment with ACEi (Lorenz, 2010).…”

Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts

“…Ang-(1-12) processing into biologically active peptides is mediated by ACE in the circulation (44) and chymase in cardiac and renal tissues (10, 20, 45). Corresponding to the heightened gene expression levels of MCP-1 and MCP-5, but not the other MCPs, in hearts of hypertensive and normotensive female rats (19), we show that these two cardiac chymase isoforms are also expressed in the heart of TGR(hAGT)L1623 rats.…”

“…Limitations in terms of experimental design, the presence of high concentrations of endogenous protease inhibitors in interstitial fluid and dismissing the fact that chymase can be sourced from either degranulation of mast cells or gene translation in myocytes, fibroblast and endothelial cells has contributed to discard this noncanonical pathway of Ang II production as a critical mechanism contributing to adverse cardiac remodeling. The void has been further aggravated by a slow pace in the development of specific chymase inhibitors, a fact that may be finally circumvented by the promising findings of recent experimental studies (45) and a published clinical trial (52, 53).…”

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

“…In immune complex-mediated glomerulonephritis, Mcpt4 chymase was shown to contribute to the inflammation and fibrosis, and the absence of Mcpt4 led to lower levels of various pathogenic factors, including Ang II, collagen 1, TNF and MCP-1/CCL2 [119]. 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].…”