Valproic Acid Upregulates SDF۱ according to Mathematical Prediction

Background: Acute kidney injury as a major health problemcan be treatable through Identifying the molecular mechanismsof tissue regeneration. In a previous study, we measured theexpression of SDF-۱, a chemokine known to be up-regulatedin injured tissues and playing an essential role in regenerationby recruiting stem cells. Unexpectedly, its declining trend wasobserved following kidney ischemia reperfusion (IR). To explainthis observation, a mathematical model was constructedand the activation of histone deacetylase was proposed as themain reason for SDF-۱ down-regulation. In order to experimentallyverify this prediction, we have here assessed the effect ofvalproic acid (VPA), a potent histone deacetylase inhibitor, onthe kinetics of SDF-۱ expression and tissue repair parameters,in a mouse model of kidney IR.Materials and Methods: Mice were subjected to IR or shamoperation and received either a single dose of VPA or normalsaline. The mRNA expression of Sdf-۱ alpha, beta, and gammawere measured in a time-course manner. Also, serum urea, creatinine,and histopathology parameters were assessed.Results: Considerable fluctuations were observed in shamgroups that disappeared following IR. Where continuous decliningtrend shows the reproducibility of our previous data.VPA induced the over-expression of gamma, but not alpha andbeta mRNA in IR mice. Although, not only did VPA not showany protective effect on kidney damage, it further aggravatedthe condition.Conclusion: The overexpression of SDF-۱ in response to VPAadministration validates the mathematical model predictionsindicating the potential of systems biology modeling tools forthe prediction of biomedical phenomena. In addition, the timecourse follow-up of all experimental groups allowed for a realisticinsight into the dynamics of the measured parameters andthe discrimination between actual responses and intrinsic variations.

کلیدواژه ها:

Acute Kidney Injury ، SDF-۱ ، Histone Deacetylase ، Valproic Acid