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Uremic toxins, accumulated during renal dysfunction, cause kidney damage, leading to renal deterioration. A recent metabolomic analysis revealed that plasma D-serine accumulation is associated with faster progression of renal dysfunction in CKD patients. However, the causal relationship and the underlying mechanisms remain unclear. Herein, we demonstrated that D-serine markedly induced cellular senescence and apoptosis in a human proximal tubular cell line, HK-2, and primary culture of human renal tubular cells. The former was accompanied by G2\/M cell cycle arrest and senescence-associated secretory phenotype, including pro-fibrotic and pro-inflammatory factors, contributing to tubulointerstitial fibrosis. Integrated stress response mediated by the general control nonderepressible 2 played an important role in D-serine-induced tubular cell toxicity and pro-fibrotic phenotypes, accelerating CKD progression and kidney aging. D-serine upregulated the L-serine synthesis pathway. Furthermore, D-serine-induced suppression of tubular cell proliferation was ameliorated by L-serine administration, indicating that D-serine exposure induced an L-serine-deprived state in tubular cells, compensated by L-serine synthesis. Thus, this study unveils molecular mechanisms underlying D-serine-induced tubular damage and pro-fibrotic phenotypes, suggesting that D-serine is a uremic toxin involved in CKD pathogenesis.<\/jats:p>","DOI":"10.1038\/s41598-017-11049-8","type":"journal-article","created":{"date-parts":[[2017,9,5]],"date-time":"2017-09-05T14:23:20Z","timestamp":1504621400000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["D-serine, a novel uremic toxin, induces senescence in human renal tubular cells via GCN2 activation"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6480-3388","authenticated-orcid":false,"given":"Akira","family":"Okada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaomi","family":"Nangaku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Ming","family":"Jao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Maekawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Ishimono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahisa","family":"Kawakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Inagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,11]]},"reference":[{"key":"11049_CR1","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.krcp.2015.08.007","volume":"34","author":"R Inagi","year":"2015","unstructured":"Inagi, R. 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