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Mitogen-Activated Protein Kinase 14 Promotes AKI
Alberto Ortiz1,2, Holger Husi3, Laura Gonzalez-Lafuente4,2
1Instituto Investigacion Sanitaria-Fundacion Jimenez Diaz-Universidad Autonoma de Madrid and Fundacion Renal Iñigo Alvarez de Toledo-Instituto Reina Sofia de Investigacion Nefrologica, Madrid, Spain; mdsanchez@fjd.es aortiz@fjd.es.
Journal of the American Society of Nephrology : JASN
|September 14, 2016
Summary
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14) promotes kidney injury by increasing inflammation and cell death. Inhibiting MAP3K14 may offer a novel therapeutic strategy for acute kidney injury (AKI).
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Understanding acute kidney injury (AKI) pathogenesis is crucial for developing new therapies.
- Previous proteomic profiling of AKI revealed potential pathways involved in kidney damage.
Purpose of the Study:
- To investigate the role of the noncanonical Nuclear Factor kappa B (NFκB) pathway in AKI.
- To identify specific molecular targets for therapeutic intervention in AKI.
Main Methods:
- Proteomic profiling using liquid chromatography-tandem mass spectrometry in a mouse model of acute folate nephropathy.
- Targeted data mining, immunohistochemistry, and Western blotting to analyze NFκB pathway components.
- Assessment of kidney injury, inflammation, and apoptosis in wild-type and MAP3K14-deficient mice.
- In vitro studies using cultured tubular cells and small interfering RNA (siRNA) targeting MAP3K14.
Main Results:
- Enrichment of NFκB pathway components, including mitogen-activated protein kinase kinase kinase 14 (MAP3K14), was identified in AKI kidneys.
- MAP3K14 expression was localized to tubular cells and its activity deficiency reduced kidney dysfunction, inflammation, and apoptosis in AKI models.
- MAP3K14 inhibition in vitro decreased inflammation and cell death, and identified chemokines MCP-1, RANTES, and CXCL10 as MAP3K14 targets.
Conclusions:
- MAP3K14 plays a significant role in promoting kidney injury by driving inflammation and cell death.
- MAP3K14 represents a promising novel therapeutic target for managing acute kidney injury.
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