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Masataka Adachi - One of the best experts on this subject based on the ideXlab platform.
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A serine protease inhibitor Camostat Mesilate prevents podocyte apoptosis and attenuates podocyte injury in metabolic syndrome model rats
'Elsevier BV', 2021Co-Authors: Teruhiko Mizumoto, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yoshikazu Miyasato, Terumasa Nakagawa, Yasunobu Iwata, Qinyuan Deng, Jun MorinagaAbstract:Metabolic syndrome (MetS) is associated with chronic kidney disease and proteinuria. Previously, we reported that a synthetic serine protease inhibitor, Camostat Mesilate (CM), mitigated hypertension and proteinuria in rodent disease models. The present study evaluated the anti-hypertensive and anti-proteinuric effects of CM in MetS model rats (SHR/ND mcr-cp). Rats were divided into normal salt-fed (NS), high salt-fed (HS), HS and CM-treated (CM), and HS and hydralazine-treated (Hyd) groups. Rats were sacrificed after four weeks of treatment. Severe hypertension and proteinuria were observed in the HS group. Although CM and Hyd equally alleviated hypertension, CM suppressed proteinuria and glomerular sclerosis more efficiently than Hyd. The HS group revealed a decrease in podocyte number and podocyte-specific molecules, together with an increase in glomerular apoptotic cells and apoptosis-related proteins in the kidney. These changes were significantly attenuated by CM, but not by Hyd. Furthermore, CM ameliorated the apoptotic signals in murine cultured podocytes stimulated with the high glucose and aldosterone medium. In conclusion, CM could exert renoprotective effects in MetS model rats, together with the inhibition of podocyte apoptosis. Our study suggests that serine protease inhibition may become a new therapeutic strategy against MetS-related hypertension and renal injuries
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a serine protease inhibitor attenuates aldosterone induced kidney injuries via the suppression of plasmin activity
Journal of Pharmacological Sciences, 2016Co-Authors: Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Terumasa Nakagawa, Tomoaki Onoue, Taku MiyoshiAbstract:Emerging evidence has suggested that aldosterone has direct deleterious effects on the kidney independently of its hemodynamic effects. However, the detailed mechanisms of these direct effects remain to be elucidated. We have previously reported that Camostat Mesilate (CM), a synthetic serine protease inhibitor, attenuated kidney injuries in Dahl salt-sensitive rats, remnant kidney rats, and unilateral ureteral obstruction rats, suggesting that some serine proteases would be involved in the pathogenesis of kidney injuries. The current study was conducted to investigate the roles of serine proteases and the beneficial effects of CM in aldosterone-related kidney injuries. We observed a serine protease that was activated by aldosterone/salt in rat kidney lysate, and identified it as plasmin with liquid chromatography-tandem mass spectrometry. Plasmin increased pro-fibrotic and inflammatory gene expressions in rat renal fibroblast cells. CM inhibited the protease activity of plasmin and suppressed cell injury markers induced by plasmin in the fibroblast cells. Furthermore, CM ameliorated glomerulosclerosis and interstitial fibrosis in the kidney of aldosterone/salt-treated rats. Our findings indicate that plasmin has important roles in kidney injuries that are induced by aldosterone/salt, and that serine protease inhibitor could provide a new strategy for the treatment of aldosterone-associated kidney diseases in humans.
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combination therapy with renin angiotensin aldosterone system inhibitor telmisartan and serine protease inhibitor Camostat Mesilate provides further renoprotection in a rat chronic kidney disease model
Journal of Pharmacological Sciences, 2016Co-Authors: Yuki Narita, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Miki Ueda, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Terumasa Nakagawa, Masataka AdachiAbstract:We previously reported that Camostat Mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.
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the serine protease inhibitor Camostat Mesilate attenuates the progression of chronic kidney disease through its antioxidant effects
Nephron, 2015Co-Authors: Miki Ueda, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yuki Narita, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Taku MiyoshiAbstract:Background/Aims: We have so far demonstrated the renoprotective effect of Camostat Mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidan
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Research Article Regulation of Adrenal Aldosterone Production by
2013Co-Authors: Serine Protease Prostasin, Yutaka Kakizoe, Naoki Wakida, Manabu Hayata, Kohei Uchimura, Naoki Shiraishi, Taku Miyoshi, Masataka Adachi, Shizuka AritomiAbstract:Copyright © 2010 Takehiro Ko et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells). Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with Camostat Mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC) inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland throug
Yutaka Kakizoe - One of the best experts on this subject based on the ideXlab platform.
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A serine protease inhibitor Camostat Mesilate prevents podocyte apoptosis and attenuates podocyte injury in metabolic syndrome model rats
'Elsevier BV', 2021Co-Authors: Teruhiko Mizumoto, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yoshikazu Miyasato, Terumasa Nakagawa, Yasunobu Iwata, Qinyuan Deng, Jun MorinagaAbstract:Metabolic syndrome (MetS) is associated with chronic kidney disease and proteinuria. Previously, we reported that a synthetic serine protease inhibitor, Camostat Mesilate (CM), mitigated hypertension and proteinuria in rodent disease models. The present study evaluated the anti-hypertensive and anti-proteinuric effects of CM in MetS model rats (SHR/ND mcr-cp). Rats were divided into normal salt-fed (NS), high salt-fed (HS), HS and CM-treated (CM), and HS and hydralazine-treated (Hyd) groups. Rats were sacrificed after four weeks of treatment. Severe hypertension and proteinuria were observed in the HS group. Although CM and Hyd equally alleviated hypertension, CM suppressed proteinuria and glomerular sclerosis more efficiently than Hyd. The HS group revealed a decrease in podocyte number and podocyte-specific molecules, together with an increase in glomerular apoptotic cells and apoptosis-related proteins in the kidney. These changes were significantly attenuated by CM, but not by Hyd. Furthermore, CM ameliorated the apoptotic signals in murine cultured podocytes stimulated with the high glucose and aldosterone medium. In conclusion, CM could exert renoprotective effects in MetS model rats, together with the inhibition of podocyte apoptosis. Our study suggests that serine protease inhibition may become a new therapeutic strategy against MetS-related hypertension and renal injuries
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a serine protease inhibitor attenuates aldosterone induced kidney injuries via the suppression of plasmin activity
Journal of Pharmacological Sciences, 2016Co-Authors: Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Terumasa Nakagawa, Tomoaki Onoue, Taku MiyoshiAbstract:Emerging evidence has suggested that aldosterone has direct deleterious effects on the kidney independently of its hemodynamic effects. However, the detailed mechanisms of these direct effects remain to be elucidated. We have previously reported that Camostat Mesilate (CM), a synthetic serine protease inhibitor, attenuated kidney injuries in Dahl salt-sensitive rats, remnant kidney rats, and unilateral ureteral obstruction rats, suggesting that some serine proteases would be involved in the pathogenesis of kidney injuries. The current study was conducted to investigate the roles of serine proteases and the beneficial effects of CM in aldosterone-related kidney injuries. We observed a serine protease that was activated by aldosterone/salt in rat kidney lysate, and identified it as plasmin with liquid chromatography-tandem mass spectrometry. Plasmin increased pro-fibrotic and inflammatory gene expressions in rat renal fibroblast cells. CM inhibited the protease activity of plasmin and suppressed cell injury markers induced by plasmin in the fibroblast cells. Furthermore, CM ameliorated glomerulosclerosis and interstitial fibrosis in the kidney of aldosterone/salt-treated rats. Our findings indicate that plasmin has important roles in kidney injuries that are induced by aldosterone/salt, and that serine protease inhibitor could provide a new strategy for the treatment of aldosterone-associated kidney diseases in humans.
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combination therapy with renin angiotensin aldosterone system inhibitor telmisartan and serine protease inhibitor Camostat Mesilate provides further renoprotection in a rat chronic kidney disease model
Journal of Pharmacological Sciences, 2016Co-Authors: Yuki Narita, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Miki Ueda, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Terumasa Nakagawa, Masataka AdachiAbstract:We previously reported that Camostat Mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.
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the serine protease inhibitor Camostat Mesilate attenuates the progression of chronic kidney disease through its antioxidant effects
Nephron, 2015Co-Authors: Miki Ueda, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yuki Narita, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Taku MiyoshiAbstract:Background/Aims: We have so far demonstrated the renoprotective effect of Camostat Mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidan
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Research Article Regulation of Adrenal Aldosterone Production by
2013Co-Authors: Serine Protease Prostasin, Yutaka Kakizoe, Naoki Wakida, Manabu Hayata, Kohei Uchimura, Naoki Shiraishi, Taku Miyoshi, Masataka Adachi, Shizuka AritomiAbstract:Copyright © 2010 Takehiro Ko et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells). Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with Camostat Mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC) inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland throug
Taku Miyoshi - One of the best experts on this subject based on the ideXlab platform.
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a serine protease inhibitor attenuates aldosterone induced kidney injuries via the suppression of plasmin activity
Journal of Pharmacological Sciences, 2016Co-Authors: Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Terumasa Nakagawa, Tomoaki Onoue, Taku MiyoshiAbstract:Emerging evidence has suggested that aldosterone has direct deleterious effects on the kidney independently of its hemodynamic effects. However, the detailed mechanisms of these direct effects remain to be elucidated. We have previously reported that Camostat Mesilate (CM), a synthetic serine protease inhibitor, attenuated kidney injuries in Dahl salt-sensitive rats, remnant kidney rats, and unilateral ureteral obstruction rats, suggesting that some serine proteases would be involved in the pathogenesis of kidney injuries. The current study was conducted to investigate the roles of serine proteases and the beneficial effects of CM in aldosterone-related kidney injuries. We observed a serine protease that was activated by aldosterone/salt in rat kidney lysate, and identified it as plasmin with liquid chromatography-tandem mass spectrometry. Plasmin increased pro-fibrotic and inflammatory gene expressions in rat renal fibroblast cells. CM inhibited the protease activity of plasmin and suppressed cell injury markers induced by plasmin in the fibroblast cells. Furthermore, CM ameliorated glomerulosclerosis and interstitial fibrosis in the kidney of aldosterone/salt-treated rats. Our findings indicate that plasmin has important roles in kidney injuries that are induced by aldosterone/salt, and that serine protease inhibitor could provide a new strategy for the treatment of aldosterone-associated kidney diseases in humans.
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the serine protease inhibitor Camostat Mesilate attenuates the progression of chronic kidney disease through its antioxidant effects
Nephron, 2015Co-Authors: Miki Ueda, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yuki Narita, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Taku MiyoshiAbstract:Background/Aims: We have so far demonstrated the renoprotective effect of Camostat Mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidan
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Research Article Regulation of Adrenal Aldosterone Production by
2013Co-Authors: Serine Protease Prostasin, Yutaka Kakizoe, Naoki Wakida, Manabu Hayata, Kohei Uchimura, Naoki Shiraishi, Taku Miyoshi, Masataka Adachi, Shizuka AritomiAbstract:Copyright © 2010 Takehiro Ko et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells). Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with Camostat Mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC) inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland throug
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Regulation of adrenal aldosterone production by serine protease prostasin.
Journal of biomedicine & biotechnology, 2010Co-Authors: Yutaka Kakizoe, Naoki Wakida, Manabu Hayata, Kohei Uchimura, Naoki Shiraishi, Taku Miyoshi, Masataka Adachi, Shizuka Aritomi, Tomoyuki KondaAbstract:A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells). Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with Camostat Mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC) inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland through the nonproteolytic action and indicate a new role of prostasin in the systemic circulation.
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Camostat Mesilate inhibits prostasin activity and reduces blood pressure and renal injury in salt-sensitive hypertension.
Journal of hypertension, 2009Co-Authors: Ai Maekawa, Kimio Tomita, Yutaka Kakizoe, Naoki Wakida, Naoki Shiraishi, Taku Miyoshi, Masataka Adachi, Kenichiro KitamuraAbstract:Prostasin, a glycosylphosphatidylinositol-anchored serine protease, regulates epithelial sodium channel (ENaC) activity. Sodium reabsorption through ENaC in distal nephron segments is a rate-limiting step in transepithelial sodium transport. Recently, proteolytic cleavage of ENaC subunits by prostasin has been shown to activate ENaC. Therefore, we hypothesized that serine protease inhibitors could inhibit ENaC activity in the kidney, leading to a decrease in blood pressure. We investigated the effects of Camostat Mesilate, a synthetic serine protease inhibitor, and FOY-251, an active metabolite of Camostat Mesilate, on sodium transport in the mouse cortical collecting duct cell line (M-1 cells) and on blood pressure in Dahl salt-sensitive rats. Treatment with Camostat Mesilate or FOY-251 decreased equivalent current (Ieq) in M-1 cells in a dose-dependent manner and inhibited the protease activity of prostasin in vitro. Silencing of the prostasin gene also reduced equivalent current in M-1 cells. The expression level of prostasin protein was not changed by application of Camostat Mesilate or FOY-251 to M-1 cells. Oral administration of Camostat Mesilate to Dahl salt-sensitive rats fed a high-salt diet resulted in a significant decrease in blood pressure with elevation of the urinary Na/K ratio, decrease in serum creatinine, reduction in urinary protein excretion, and improvement of renal injury markers such as collagen 1, collagen 3, transforming growth factor-beta1, and nephrin. These findings suggest that Camostat Mesilate can decrease ENaC activity in M-1 cells probably through the inhibition of prostasin activity, and that Camostat Mesilate can have beneficial effects on both hypertension and kidney injury in Dahl salt-sensitive rats. Camostat Mesilate might represent a new class of antihypertensive drugs with renoprotective effects in patients with salt-sensitive hypertension.
Norio Sawabu - One of the best experts on this subject based on the ideXlab platform.
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effect of Camostat Mesilate on the expression of pancreatitis associated protein pap p8 and cytokines in rat spontaneous chronic pancreatitis
Pancreas, 2001Co-Authors: Yoshiharu Motoo, Min-jue Xie, Juan L. Iovanna, Norio SawabuAbstract:An oral protease inhibitor, Camostat Mesilate (CM) has been used clinically for chronic pancreatitis (CP) in Japan, but it lacks enough scientific evidence of its effectiveness. The aim of this study was to analyze the effect of CM on the gene expressions of pancreatitis-associated protein (PAP), p8, and cytokines such as interleukin-6 and transforming growth factor-beta1 in spontaneous CP model (WBN/Kob rats). CM (10 mg/100 g body weight), mixed in MB-3 diet, was administered orally and gene expressions were analyzed by reverse transcription-polymerase chain reaction. In untreated WBN/Kob rats, the gene expressions of all the four factors peaked at 12 weeks, whereas they were significantly suppressed in the CM-treated rats. CM significantly increased the body weight and pancreatic wet weight, and it significantly inhibited inflammatory changes and fibrosis of the pancreas. These results suggest that CM inhibits pancreatic inflammation and fibrosis through the suppression of gene expressions of PAP, p8, and cytokines in CP.
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Effect of Camostat Mesilate on the expression of pancreatitis-associated protein (PAP), p8, and cytokines in rat spontaneous chronic pancreatitis.
Pancreas, 2001Co-Authors: Yoshiharu Motoo, Min-jue Xie, Juan L. Iovanna, Norio SawabuAbstract:Summary:An oral protease inhibitor, Camostat Mesilate (CM) has been used clinically for chronic pancreatitis (CP) in Japan, but it lacks enough scientific evidence of its effectiveness. The aim of this study was to analyze the effect of CM on the gene expressions of pancreatitis-associated protein (
Kohei Uchimura - One of the best experts on this subject based on the ideXlab platform.
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A serine protease inhibitor Camostat Mesilate prevents podocyte apoptosis and attenuates podocyte injury in metabolic syndrome model rats
'Elsevier BV', 2021Co-Authors: Teruhiko Mizumoto, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yoshikazu Miyasato, Terumasa Nakagawa, Yasunobu Iwata, Qinyuan Deng, Jun MorinagaAbstract:Metabolic syndrome (MetS) is associated with chronic kidney disease and proteinuria. Previously, we reported that a synthetic serine protease inhibitor, Camostat Mesilate (CM), mitigated hypertension and proteinuria in rodent disease models. The present study evaluated the anti-hypertensive and anti-proteinuric effects of CM in MetS model rats (SHR/ND mcr-cp). Rats were divided into normal salt-fed (NS), high salt-fed (HS), HS and CM-treated (CM), and HS and hydralazine-treated (Hyd) groups. Rats were sacrificed after four weeks of treatment. Severe hypertension and proteinuria were observed in the HS group. Although CM and Hyd equally alleviated hypertension, CM suppressed proteinuria and glomerular sclerosis more efficiently than Hyd. The HS group revealed a decrease in podocyte number and podocyte-specific molecules, together with an increase in glomerular apoptotic cells and apoptosis-related proteins in the kidney. These changes were significantly attenuated by CM, but not by Hyd. Furthermore, CM ameliorated the apoptotic signals in murine cultured podocytes stimulated with the high glucose and aldosterone medium. In conclusion, CM could exert renoprotective effects in MetS model rats, together with the inhibition of podocyte apoptosis. Our study suggests that serine protease inhibition may become a new therapeutic strategy against MetS-related hypertension and renal injuries
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a serine protease inhibitor attenuates aldosterone induced kidney injuries via the suppression of plasmin activity
Journal of Pharmacological Sciences, 2016Co-Authors: Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Terumasa Nakagawa, Tomoaki Onoue, Taku MiyoshiAbstract:Emerging evidence has suggested that aldosterone has direct deleterious effects on the kidney independently of its hemodynamic effects. However, the detailed mechanisms of these direct effects remain to be elucidated. We have previously reported that Camostat Mesilate (CM), a synthetic serine protease inhibitor, attenuated kidney injuries in Dahl salt-sensitive rats, remnant kidney rats, and unilateral ureteral obstruction rats, suggesting that some serine proteases would be involved in the pathogenesis of kidney injuries. The current study was conducted to investigate the roles of serine proteases and the beneficial effects of CM in aldosterone-related kidney injuries. We observed a serine protease that was activated by aldosterone/salt in rat kidney lysate, and identified it as plasmin with liquid chromatography-tandem mass spectrometry. Plasmin increased pro-fibrotic and inflammatory gene expressions in rat renal fibroblast cells. CM inhibited the protease activity of plasmin and suppressed cell injury markers induced by plasmin in the fibroblast cells. Furthermore, CM ameliorated glomerulosclerosis and interstitial fibrosis in the kidney of aldosterone/salt-treated rats. Our findings indicate that plasmin has important roles in kidney injuries that are induced by aldosterone/salt, and that serine protease inhibitor could provide a new strategy for the treatment of aldosterone-associated kidney diseases in humans.
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combination therapy with renin angiotensin aldosterone system inhibitor telmisartan and serine protease inhibitor Camostat Mesilate provides further renoprotection in a rat chronic kidney disease model
Journal of Pharmacological Sciences, 2016Co-Authors: Yuki Narita, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Miki Ueda, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Terumasa Nakagawa, Masataka AdachiAbstract:We previously reported that Camostat Mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.
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the serine protease inhibitor Camostat Mesilate attenuates the progression of chronic kidney disease through its antioxidant effects
Nephron, 2015Co-Authors: Miki Ueda, Yutaka Kakizoe, Manabu Hayata, Kohei Uchimura, Masataka Adachi, Yuki Narita, Yoshikazu Miyasato, Teruhiko Mizumoto, Jun Morinaga, Taku MiyoshiAbstract:Background/Aims: We have so far demonstrated the renoprotective effect of Camostat Mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidan
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Research Article Regulation of Adrenal Aldosterone Production by
2013Co-Authors: Serine Protease Prostasin, Yutaka Kakizoe, Naoki Wakida, Manabu Hayata, Kohei Uchimura, Naoki Shiraishi, Taku Miyoshi, Masataka Adachi, Shizuka AritomiAbstract:Copyright © 2010 Takehiro Ko et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells). Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with Camostat Mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC) inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland throug