Valproic acid restores the down-regulation of SDF-1 following kidney ischemia; experimental validation of a mathematical prediction

Abstract

Background and purpose: Stromal-derived factor (SDF)-1, a chemokine recruiting leucocytes and stem cells, plays an essential role in tissue regeneration. In aprevious study, we have unexpectedly found that the expression of this chemokine declines following kidney ischemia reperfusion (IR). To explain this observation, a mathematical model was constructed which proposed histone deacetylase (HDAC) as the main driver of SDF-1 down-regulation. To experimentally verify this prediction, the effect of valproic acid (VPA), a potent HDAC inhibitor, on the kinetics of kidney SDF-1 expression was here assessed. Experimental approach: Adult mice were subjected to IR or sham operation and received VPA or vehicle. Next, SDF-1 expression as well as tissue repair indices were measured in a time course manner. Findings / Results: The transcriptional expressions of Sdf-1 alpha, beta, and gamma isoforms were noisy in the sham groups but the fluctuations disappeared following IR where a continuous declining trend was observed. VPA induced the over-expression of gamma, but not alpha and beta mRNA in IR mice which was accompanied with protein upregulation. Remarkably, VPA deteriorated kidney injury. Conclusion and implications: HDAC inhibition restores SDF-1 down-regulation following kidney IR. The present study is a classic example of the potential of computational modeling for the prediction of biomedical phenomena.

Keywords

• acute kidney injury; histone deacetylase
• ischemia reperfusion injury; sdf-1; valproic acid.