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dc.contributor.authorHsieh, Wen-Yehen_US
dc.contributor.authorChang, Teng-Hsiangen_US
dc.contributor.authorChang, Hui-Fangen_US
dc.contributor.authorChuang, Wan-Hsuanen_US
dc.contributor.authorLu, Li-Cheen_US
dc.contributor.authorYang, Chung-Weien_US
dc.contributor.authorLin, Chih-Shengen_US
dc.contributor.authorChang, Chia-Chuen_US
dc.date.accessioned2019-04-02T06:01:05Z-
dc.date.available2019-04-02T06:01:05Z-
dc.date.issued2019-01-11en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0210656en_US
dc.identifier.urihttp://hdl.handle.net/11536/148708-
dc.description.abstractAngiotensin-converting enzyme (ACE) is the primary enzyme that converts angiotensin I (Ang I) to angiotensin II (Ang II) in the renin-angiotensin system (RAS). However, chymase hydrates Ang I to Ang II independently of ACE in some kidney diseases, and it may play an important role. The present study investigated whether chymase played a crucial role in aristolochic acid I (AAI)-induced nephropathy. C57BL/6 mice were treated with AAI via intraperitoneal injection for an accumulated AAI dosage of 45 mg/kg body weight (BW) (15 mg/kg BW per day for 3 days). The animals were sacrificed after acute kidney injury development, and blood, urine and kidneys were harvested for biochemical and molecular assays. Mice exhibited increased serum creatinine, BUN and urinary protein after the AAI challenge. Significant infiltrating inflammatory cells and tubular atrophy were observed in the kidneys, and high immunocytokine levels were detected. Renal RAS-related enzyme activities were measured, and a significantly increased chymase activity and slightly decreased ACE activity were observed in the AAI-treated mice. The renal Ang II level reflected the altered profile of RAS enzymes and was significantly increased in AAI-treated mice. Treatment of AAI-induced nephropathic mice with an ACE inhibitor (ACEI) or chymase inhibitor (CI; chymostatin) reduced renal Ang II levels. The combination of ACEI and CI (ACEI+CI) treatment significantly reversed the AAI-induced changes of Ang II levels and kidney inflammation and injuries. AAI treatment significantly increased renal p-MEK without increasing p-STAT3 and p-Smad3 levels, and p-MEK/p-ERK1/2 signalling pathway was significantly activated. CI and ACEI+CI treatments reduced this AAI-activated signaling pathway. AAI-induced nephropathy progression was significantly mitigated with CI and ACEI+CI treatment. This study elucidates the role of RAS in the pathogenesis of AAI-induced nephropathy.en_US
dc.language.isoen_USen_US
dc.titleRenal chymase-dependent pathway for angiotensin II formation mediated acute kidney injury in a mouse model of aristolochic acid I-induced acute nephropathyen_US
dc.typeArticleen_US
dc.identifier.doi10.1371/journal.pone.0210656en_US
dc.identifier.journalPLOS ONEen_US
dc.citation.volume14en_US
dc.contributor.department交大名義發表zh_TW
dc.contributor.department生物科技學系zh_TW
dc.contributor.departmentNational Chiao Tung Universityen_US
dc.contributor.departmentDepartment of Biological Science and Technologyen_US
dc.identifier.wosnumberWOS:000455485100034en_US
dc.citation.woscount0en_US
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