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The effect of the chymase inhibitor TY-51469 on the development and progression of non-alcoholic steatohepatitis (NASH) was evaluated in rats fed a high-fat and high-cholesterol (HFC) diet. To evaluate the preventive effect of TY-51469 on the development of NASH, stroke-prone spontaneously hypertensive rat 5 (SHRSP5)/Dmcr rats were fed either a normal or HFC diet for 8 weeks, and concurrently administered either placebo or TY-51469 (1 mg/kg per day). To evaluate the effect of TY-51469 on the survival rate, TY-51469 was administered either concurrently with HFC diet (pretreated group) or 8 weeks after HFC diet at which point NASH had developed (posttreated group). Eight weeks after HFC diet, significant increases of steatosis, fibrosis and chymase-positive cells were observed in liver from the placebo-treated rats. Significant increases of myeloperoxidase, transforming growth factor-β, matrix metalloproteinase-9, and collagen I mRNA levels were also observed. However, all parameters were significantly attenuated in the TY-51469-treated group. A survival rate of the placebo-treated group fed the HFC diet was 0% at 14 weeks. In comparison, the rates of TY-51469-pretreated and TY-51469-posttreated groups were 100% and 50% at 14 weeks, respectively. Chymase inhibitor may be applicable to preventing the development and progression of NASH., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Angiotensin II plays an important role in regulating blood pressure. Moreover, angiotensin II directly promotes organ damage by inducing expression of various genes, such as transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 precursors. Blockade of angiotensin II has been shown to not only lower blood pressure, but also to prevent cardiovascular and renal dysfunction and fibrosis. Inhibition of TGF-β and MMP-9 has also been shown to prevent cardiovascular and renal damage. A mast cell-produced enzyme, chymase, generates angiotensin II and also converts precursors of TGF-β and MMP-9 to their active forms. Chymase also strongly promotes accumulation of inflammatory cells. These multiple functions of chymase may play an important role in the development and promotion of various diseases. In fact, chymase inhibitors have been shown to prevent nonalcoholic steatohepatitis, intestinal inflammation, and adhesion formation after surgery and cardiovascular and renal damage. On the other hand, chymase inhibitors, unlike angiotensin-converting enzyme inhibitors and angiotensin II blockers, have no blood pressure-lowering effect despite blocking angiotensin II formation. Thus, chymase inhibitors may be useful for preventing damage to various organs via multiple mechanisms without lowering blood pressure.

Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expression of transforming growth factor (TGF)-beta and matrix metalloproteinase (MMP)-9 precursors, and chymase can convert precursors of TGF-beta and MMP-9 to their active forms. In cultured fibroblasts, significant increases in cell growth and TGF-beta levels were observed after chymase injection; these increases were inhibited by a chymase inhibitor, but not by an angiotensin II-receptor blocker. In apolipoprotein E-deficient mice, abdominal aortic aneurysm (AAA) development depends on an increase in MMP-9 activities induced by angiotensin II infusion, but the inhibition of MMP-9 activation by a chymase inhibitor resulted in attenuation of the angiotensin II-induced AAA development. The upregulation of MMP-9 and TGF-beta levels is involved in damage to various organs, but these gene expressions are not completely induced by angiotensin II alone. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-beta levels, in addition to reducing angiotensin II formation, and this function may provide powerful organ protection. In this review, we propose the possible use of chymase inhibitors as agents to prevent organ damage.

Recent studies indicate a role of chymase in the regulation of angiotensin II (AngII) formation in cardiovascular and renal tissues. We investigated a possible contribution of chymase to AngII formation and to renal fibrosis in unilateral ureteral obstruction (UUO). Eight-week-old Syrian hamsters were subjected to UUO and treated with vehicle, the specific chymase inhibitor (CI) 4-[1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1H-benzimidazol-2-ylsulfanyl]-butyric acid (50 mg/kg, twice a day, p.o.), or the selective AT(1)-receptor blocker olmesartan (10 mg/kg per day, p.o.) for 14 days. UUO-induced renal interstitial fibrosis was associated with increases in renal mRNA levels of alpha-smooth muscle actin (SMA), type I collagen, and transforming growth factor (TGF)-beta. The UUO hamsters showed markedly higher AngII contents and increased AT(1)-receptor mRNA level in the obstructed kidney than sham-operated ones. In contrast, angiotensin-converting enzyme (ACE) protein expression was significantly lower in UUO hamsters. In UUO hamsters, treatment with CI or olmesartan significantly decreased AngII levels in renal tissue and mRNA levels of alpha-SMA, type I collagen, and TGF-beta and ameliorated tubulointerstitial injury. On the other hand, neither CI nor olmesartan changed systolic blood pressure, renal ACE, and AT(1)-receptor protein levels. These data suggest that chymase-dependent intrarenal AngII formation contributes to the pathogenesis of interstitial fibrosis in obstructed kidneys of hamsters.

Angiotensin II may be involved in pancreatic disorganization, but the involvement of chymase has been unclear. In the present study, we examined whether chymase is involved in pancreatic disorganization in hamsters with streptozotocin (STZ)-induced diabetes. Hamsters were injected with streptozotocin (60 mg/kg), and non-injected hamsters served as controls. To investigate the effect of a chymase inhibitor, TY-51469 (30 mg/kg per day), hamsters in the STZ group were administered TY-51469 or placebo from 2 weeks after STZ injection, for 1 week. A significant increase in blood glucose level was observed at 1 week after STZ injection. This was maintained at 2 weeks, and a further significant increase was observed at 3 weeks. Until 2 weeks after STZ injection, all angiotensin II-related enzyme activities were unchanged, but at 3 weeks pancreatic chymase and total angiotensin II-forming activities, but not angiotensin-converting enzyme activity, were significantly increased. TY-51469 significantly attenuated blood glucose level along with reductions of chymase and total angiotensin II-forming activities and malondialdehyde level. Furthermore, there were significantly more pancreatic islets in the TY-51469 group than in the placebo group. In conclusion, chymase inhibition might protect against pancreatic islet disorganization.