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The Role of p204 in Kidney Injury
Author(s) -
Marlier Arnaud,
Huen Sarah,
Lengyel Peter,
Cantley Lloyd
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.807.1
Subject(s) - medicine
Kidney ischemia can lead to acute kidney injury (AKI) caused by tubular cell necrosis, which in turn can promote kidney fibrosis and in some cases progress to chronic kidney disease (CKD). Hence understanding the molecular and cellular pathways involved becomes crucial if we want to manipulate them to improve outcomes. p204 is a member of the interferon inducible family of p200 proteins that has been shown to regulate cell differentiation, proliferation and inflammasome activation. These functions prompted us to investigate the role of p204 in kidney injury and repair. We observed an up‐regulation of both the p204 mRNA and protein when mice were subjected to renal ischemia‐reperfusion injury (IRI), predominantly during the reparative phase. Cell sorting analysis indicated that predominantly CD45 positive cells, including macrophages, were expressing p204. We generated a whole body knockout of p204 (p204 fl/fl ; ACTB‐Cre), which exhibited no obvious development abnormalities nor fertility defects. However, following renal IRI, p204ko mice had lower peak serum creatinine levels than did wild type (WT) controls. Among the AKI biomarkers analyzed, we found greater upregulation of the cytoprotective protein chitinase3‐like 1 (Chi3l1) in p204ko as compared to WT controls. In vitro, we confirmed that bone marrow derived macrophages (BMDM) increased p204 expression in response to classical inflammatory stimuli such as DAMPS, LPS or INFG, and that Chi3l1 expression was significantly increased in p204ko BMDM as compared to WT BMDM under the same conditions. These findings suggest that both in vivo and in vitro, p204 represses the expression of the anti‐apoptotic protein Chi3l1 and thus could serve as a therapeutic target to improve outcomes following AKI.