Ortiz A, Husi H, Gonzalez-Lafuente L, Valino-Rivas L, Fresno M, Sanz AB, Mullen W, Albalat A, Mezzano S, Vlahou A, Mischak H & Sanchez-Nino MD (2017) Mitogen-Activated Protein Kinase 14 Promotes AKI. Journal of the American Society of Nephrology, 28 (3), pp. 823-836. https://doi.org/10.1681/ASN.2015080898
An improved understanding of pathogenic pathways may identify novel acute kidney injury (AKI) therapeutic approaches. Unbiased LC-MS/MS protein expression profiling combined with focused data mining identified MAP3K14 and non-canonical NFκB activation at the crossroads of the enriched pathways MAPK, ubiquitin-mediated proteolysis, chemokines, NFκB and apoptosis in the kidney cortex of experimental toxic AKI. In AKI the upstream kinase MAP3K14, the NFκB DNA binding heterodimer RelB/NFκB2, and proteins involved in NFκB2 p100 ubiquitination and proteasomal processing to p52, such as Ube2m and cullin1 were up-regulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in experimental and human AKI. In vivo evidence of MAP3K14 activation in experimental folic acid-induced AKI consisted of NFκB2 p100 processing to p52, nuclear location and DNA binding of RelB and NFκB2. MAP3K14 activity-deficient aly/aly mice were protected from kidney dysfunction, inflammation and apoptosis in AKI induced by folic acid and from lethality in cisplatin-induced AKI. MAP3K14 siRNA targeting in cultured tubular cells decreased inflammation and cell death. Bone marrow transplantation experiments where consistent with a protective effect of renal cell MAP3K14 targeting. Cell culture and in vivo studies identified chemokines MCP-1, RANTES and CXCL10 as MAP3K14 targets in tubular cells, thus identifying potential mediators of the deleterious effect of MAP3K14 in kidney injury. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target.
acute kidney injury; apoptosis; inflammation; MAP3K14; NIK; non-canonical NFκB; tissue proteomics
Journal of the American Society of Nephrology: Volume 28, Issue 3
|Publication date online||12/09/2016|
|Date accepted by journal||28/07/2016|
|Publisher||American Society of Nephrology|