Acute kidney injury transcriptomics unveils a relationship between inflammation and ageing.
2012
There are no pathophysiolgical therapeutic approaches to
acute kidney injury (AKI) and the mortality remains high. In
addition chronic kidney disease (CKD) predisposes to AKI
and AKI contributes to progression of CKD. Recently a transcriptomics
approach unveiled a relationship between AKI,
inflammation and the regulation of ageing. A transcriptomics
analysis of experimental AKI revealed increased kidney
expression of Fn14 and transmembrane chemokine CXCL16,
as well as a decreased expression of the kidney-secreted
anti-ageing hormone Klotho. Fn14 is the receptor for tumor
necrosis factor-like weak inducer of apoptosis (TWEAK), a
member of the TNF superfamily. In AKI kidneys there was a
positive correlation between Fn14 and CXCL16 mRNA expression
and an inverse correlation between Fn14 and Klotho
mRNA. Tubular cells were the site of Fn14, CXCL16 and
Klotho expression in vivo. Research on the relationships between
these three molecules disclosed that TWEAK activation
of Fn14 promoted inflammation through secretion of
chemokines such as CXL16 in tubular cells in culture and in
vivo. Furthermore, TWEAK activation of Fn14 decreased expression
of Klotho mRNA and protein in culture and in vivo.
Interestingly, both TWEAK activation of CXCL16 mRNA
transcription and suppression of Klotho mRNA transcription
were mediated by the NFeB transcription factor. In conclusion,
TWEAK engagement of Fn14 is a central event promoting
NFeB-mediated activation of inflammation pathways
and suppression of anti-inflammatory/anti-ageing pathways.
This information may influence future therapeutic approaches
to AKI and inflammation/aging.
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