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This study investigated the effect of co\u2010treatment using erythropoietin\u2010derived helix B surface peptide (HBSP) and caspase\u20103 small interfering RNA (CASP3siRNA) on preventing fibrosis post AKI in order to achieve better efficacy by different action mechanisms. Ischemia\u2013reperfusion (IR) in mice was induced by clamping bilateral renal pedicles for 30\u2009min followed by 2\u2010week reperfusion, with HBSP and\/or CASP3siRNA administered at the onset of IR. Serum creatinine, apoptosis, active caspase\u20103 and high mobility group protein B1 (HMGB1) in kidneys were decreased by HBSP, CASP3siRNA or both, with increased PCNA. \u03b1\u2010SMA expression and collagen I deposition were also reduced by CASP3siRNA and both. Most interestingly, the co\u2010treatment further reduced tubulointerstitial damage and fibrosis, but raised PCNA compared to CASP3siRNA. EPOR\/\u03b2cR was reduced by HBSP, and positively correlated with Sirius red staining, whereas EPOR was unchanged. In TCMK\u20101 cells, H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> raised apoptosis and \u03b1\u2010SMA were reduced by HBSP, while the same was occurred to HMGB1. However, HMGB1 was further increased by EPOR siRNA under H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> stimulation with\/without HBSP treatment. In conclusion, this study demonstrated synergistic long\u2010term renoprotection post IR\u2010AKI by HBSP and CASP3siRNA, which may be due to co\u2010inhibiting inflammation and stimulating repair at early stage, and subsequently preventing fibrosis.<\/jats:p>","DOI":"10.1111\/jcmm.70082","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T08:58:56Z","timestamp":1733302736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Co\u2010treatment with erythropoietin derived <scp>HBSP<\/scp> and caspase\u20103 <scp>siRNA<\/scp>: A promising approach to prevent fibrosis after acute kidney injury"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6253-7773","authenticated-orcid":false,"given":"Yuanyuan","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pathology Medical School, Nantong University  Nantong China"},{"name":"Department 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