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Herein we demonstrated evidence that CHOP-related ER stress is associated with the development of renal fibrosis in both CKD patients and unilateral ureteral obstruction (UUO)-induced animals, and specifically, mice deficient in <jats:italic>Chop<\/jats:italic> were protected from UUO-induced renal fibrosis. Mechanistic studies revealed that loss of <jats:italic>Chop<\/jats:italic> protected tubular cells from UUO-induced apoptosis and secondary necrosis along with attenuated Hmgb1 passive release and active secretion. As a result, <jats:italic>Chop<\/jats:italic> deficiency suppressed Hmgb1\/TLR4\/NF<jats:italic>\u03ba<\/jats:italic>B signaling, which then repressed UUO-induced IL-1<jats:italic>\u03b2<\/jats:italic> production. Consequently, the IL-1<jats:italic>\u03b2<\/jats:italic> downstream Erk1\/2 activity and its related c-Jun transcriptional activity were reduced, leading to attenuated production of TGF-<jats:italic>\u03b2<\/jats:italic>1 following UUO insult. It was further noted that reduced IL-1<jats:italic>\u03b2<\/jats:italic> production also inhibited UUO-induced PI3K\/AKT signaling, and both of which ultimately protected mice from UUO-induced renal fibrosis. Together, our data support that suppression of CHOP expression could be a viable therapeutic strategy to prevent renal fibrosis in patients with CKDs.<\/jats:p>","DOI":"10.1038\/cddis.2015.206","type":"journal-article","created":{"date-parts":[[2015,8,6]],"date-time":"2015-08-06T15:49:19Z","timestamp":1438876159000},"page":"e1847-e1847","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":101,"title":["Chop deficiency prevents UUO-induced renal fibrosis by attenuating fibrotic signals originated from Hmgb1\/TLR4\/NF\u03baB\/IL-1\u03b2 signaling"],"prefix":"10.1038","volume":"6","author":[{"given":"M","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J-F","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Pei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C-Y","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,8,6]]},"reference":[{"key":"BFcddis2015206_CR1","doi-asserted-by":"publisher","first-page":"255","DOI":"10.2215\/CJN.01150113","volume":"9","author":"G Pei","year":"2014","unstructured":"Pei G, Zeng R, Han M, Liao P, Zhou X, Li Y et al. 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