A serine protease inhibitor camostat mesilate prevents podocyte apoptosis and attenuates podocyte injury in metabolic syndrome model rats

Mizumoto, Teruhiko; Kakizoe, Yutaka; Nakagawa, Terumasa; Iwata, Yasunobu; Miyasato, Yoshikazu; Uchimura, Kohei; Adachi, Masataka; Deng, Qinyuan; Hayata, Manabu; Morinaga, Jun; Miyoshi, Takuji; Yokoyama, Izumi; Kuwabara, Tomohiko; Sakai, Yoshiki; Tomita, Kimio; Kitamura, Kenichiro; Mukoyama, Masashi

doi:10.1016/j.jphs.2021.04.003

Cited by 5 publications

(6 citation statements)

References 28 publications

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“…The HS group exhibited substantial proteinuria, which was significantly attenuated by CM (Figure 1B). Both PRA and PAC were markedly suppressed by the HS diet, while CM had no effect, which is consistent with our previous findings (Figure 1C) [13]. Cardiac and renal hypertrophies were provoked in the HS group, whereas CM administration tended to reduce cardiac hypertrophy and significantly suppressed renal hypertrophy (Table 1).…”

Section: Resultssupporting

confidence: 92%

“…Camostat mesilate (CM), a synthetic serine protease inhibitor developed in Japan, has been used clinically for several decades to treat conditions such as chronic pancreatitis and reflux esophagitis after surgery [8]. We have previously demonstrated the blood pressure-lowering and renoprotective effects of CM in rodent models of hypertension and chronic kidney disease (CKD) [9][10][11][12][13]. In our past study, we observed that plasmin is activated in the kidney of aldosterone and salt-treated rats, and CM mitigated hypertension and renal damage in association with the inhibition of plasmin activity [12].…”

Section: Introductionmentioning

confidence: 99%

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A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

Iwata,

Deng,

Kakizoe

et al. 2023

IJMS

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In proteinuric renal diseases, the serine protease (SP) plasmin activates the epithelial sodium channel (ENaC) by cleaving its γ subunit. We previously demonstrated that a high-salt (HS) diet provoked hypertension and proteinuria in Dahl salt-sensitive (DS) rats, accompanied by γENaC activation, which were attenuated by camostat mesilate (CM), an SP inhibitor. However, the effects of CM on plasmin activity in DS rats remain unclear. In this study, we investigated the effects of CM on plasmin activity, ENaC activation, and podocyte injury in DS rats. The DS rats were divided into the control diet, HS diet (8.0% NaCl), and HS+CM diet (0.1% CM) groups. After weekly blood pressure measurement and 24-h urine collection, the rats were sacrificed at 5 weeks. The HS group exhibited hypertension, massive proteinuria, increased urinary plasmin, and γENaC activation; CM treatment suppressed these changes. CM prevented plasmin(ogen) attachment to podocytes and mitigated podocyte injury by reducing the number of apoptotic glomerular cells, inhibiting protease-activated receptor-1 activation, and suppressing inflammatory and fibrotic cytokine expression. Our findings highlight the detrimental role of urinary plasmin in the pathogenesis of salt-sensitive hypertension and glomerular injury. Targeting plasmin with SP inhibitors, such as CM, may be a promising therapeutic approach for these conditions.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

Iwata,

Deng,

Kakizoe

et al. 2023

IJMS

Self Cite

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“…In a rat model of a metabolic syndrome, severe hypertension and proteinuria were observed in rats fed with a high-salt diet. Hydralazine was shown to alleviate hypertension, decrease urinary protein excretion, and reduce the glomerular sclerosis level [ 21 , 22 ]. Accordingly, it seems that hydralazine may provide effective renal protection across different CKD models.…”

Section: Potential Effects Of Hydralazine On Kidney Diseasementioning

confidence: 99%

Potential Impacts of Hydralazine as a Novel Antioxidant on Cardiovascular and Renal Disease—Beyond Vasodilation and Blood Pressure Lowering

Chang

Chen

2022

Antioxidants

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Hydralazine is a traditional antihypertensive drug that was developed several decades ago. Its most well-known effect is blood pressure lowering by arterial vasodilation. While mainly used an adjunct treatment for clinical hypertension or chronic heart failure, this old drug has also shown potential as a repurposing drug for the atherosclerosis vascular disease and various kidney diseases. Recent experimental studies suggest that hydralazine exerts antioxidative, anti-apoptotic, and HIF-1α stabilization effects for angiogenesis and vascular protection. Hydralazine also exerts reno-protective effects via its antioxidation, DNA demethylation, and anti-inflammation abilities. The above evidence provides advanced rationales for new applications of this drug beyond blood pressure lowering and arterial vasodilation. Here, we summarized the recent experimental advances in the use of hydralazine for either a vascular disease or kidney diseases, or both. Given the wide populations of people with cardiovascular and/or kidney diseases, future studies are worth validating the potential impacts of hydralazine on the clinical outcomes in selected patients.

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“…Camostate inhibits in vitro various pancreatic and plasmatic proteolytic enzymes such as trypsin, plasmin, pancreatic kallikrein, plasma kallikrein, and thrombin, as well as the hydrolytic activity of C1r and C1 esterase [33,36]. Camostate further inhibits the cellular protease TMPRSS2 in vitro [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][20][21][22][23][24][25][26][27][28][29][31][32]34,35]. The efficacy of Camostate in different cell cultures has already been demonstrated .…”

mentioning

confidence: 99%

“…Camostates inhibits TMPRSS2, the enzyme is expressed on the human cell surface after autocatalytic activation, mainly in the small intestine and to a lesser extent in the liver, heart, prostate, thymus and lung . As per the analysis, SARS-CoV-2, virus responsible for the COVID-19, requires TMPRSS2 exists in human body to get inside the host cell, which may provide target for the treatment [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][20][21][22][23][24][25][26][27][28][29]31,32,34,35]. Therapeutic efficacy in COVID-19 patients remains to be tested in clinical trials [2][3][4]6,24,32].…”

mentioning

confidence: 99%

A Present Update of Camostate and the Role in SARS-CoV-2 Infection

Bittmann¹

2022

Journal of Clinical Pediatrics Research

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SARS-CoV-2 has triggered a pandemic of "coronavirus disease-2019" (Covid-19). Viral cell entry of coronaviruses relies on the binding of viral spike protein (S protein) to cellular receptors and S type of protein processing by the host cell proteases. It is known that SARS-CoV-2 uses the human receptor ACE2 for cell entry and the serine protease TMPRSS2 for "priming" of the S protein. Camostate has antiviral properties against coronaviruses. The effects are due to inhibition of the endogenous protease TMPRSS2, which the SARS-CoV-2 virus requires for the host cell entry (as well as exit). Camostate is a serine protease inhibitor. Camostate, which is already in clinical use, reduces cell infection. So far, this has been shown exclusively in cell lines or cell cultures, which do not reflect the complexity of the three-dimensional alveolar lung cell association with type I, type II cells, endothelial cells and alveolar macrophages.It is well known, that Camostate blocks TMPRSS2 and related proteases [1-36]. For SARS-CoV-2 to enter lung cells, the virus must be activated by the cellular protease TMPRSS2. Camostateis used in Japan to treat inflammation of the pancreas, blocks the protease TMPRSS2 and thereby inhibit SARS-CoV-2[1-18,20-29,31-35]. However, it was unclear whether the camostate degradation product GBPA also inhibits the virus and whether the virus can use related proteases for infection in addition to TMPRSS2, which may not be inhibited by camostate[18,20,29]. These proteases are available to the virus for replication in the upper respiratory tract and are inhibited by camostate[1-36]. It is therefore not possible for SARS-CoV-2 to evade the antiviral effect of Camostate by switching to related proteases instead of TMPRSS2. In further studies, the researchers were able to show that in addition to Camostate, the primary Camostate metabolite GBPA also inhibits the protease TMPRSS2, thereby blocking SARS-CoV-2 infection. Camostate is converted to GBPA in the body within a very short time.GBPA can exert an antiviral effect in patients. A higher dosage of Camostate to effectively treat COVID-19 than to treat pancreatic inflammation may be required [33,36]. Inhibition of SARS-CoV-2 by Camostate had initially been shown only in the lung cell line Calu-3[6]. The involvement of researchers from Hannover, Germany, made it possible to analyze the antiviral effect of Camostatein real lung tissue as well [6]. Camostate and GBPA inhibit SARS-CoV-2 infection of lung tissue [15]. The camostatemesilate-containing drug Foipan® has been available on the Japanese market since 1986 [1-36]. It is used to treat chronic inflammation of the pancreas and postoperative reflux esophagitis [33,36]. According to the product information, the substance has an inhibitory effect on several enzymes and intervenes in various systems in the body. Among other things, an inhibitory effect on trypsin and normalization of amylase levels are mentioned [33,36]. However, the reason why this substance suddenly becomes interesting in the corona crisis is different [24,26,30].

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A serine protease inhibitor camostat mesilate prevents podocyte apoptosis and attenuates podocyte injury in metabolic syndrome model rats

Cited by 5 publications

References 28 publications

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

Potential Impacts of Hydralazine as a Novel Antioxidant on Cardiovascular and Renal Disease—Beyond Vasodilation and Blood Pressure Lowering

A Present Update of Camostate and the Role in SARS-CoV-2 Infection

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