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

Kobra Moradzadeh , Seyed Mahdi Nassiri, Yousof Gheisari


Background and purpose: Stromal-derived factor (SDF)-1, a chemokine recruiting leucocytes and stem cells, plays an essential role in tissue regeneration. In a previous 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.



Acute kidney injury; Histone deacetylase, Ischemia reperfusion injury; SDF-1; Valproic acid.

Full Text:



Hoste EA, Schurgers M. Epidemiology of acute kidney injury: how big is the problem? Crit Care Med. 2008;36(4 Suppl):S146-S151.

DOI: 10.1097/CCM.0b013e318168c590.

Li PKT, Burdmann EA, Mehta RL, World Kidney Day Steering Committee 2013. Acute kidney injury: global health alert. Kidney Int. 2013;83(3):372-376.

DOI: 10.1038/ki.2012.427.

Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, et al. Acute kidney injury: an increasing global concern. Lancet. 2013;382(9887):170-179.

DOI: 10.1016/S0140-6736(13)60647-9.

Bellomo R, Kellum JA, Ronco C. Acute kidney injury. The Lancet. 2012;380(9843):756-766.

Erpicum P, Rowart P, Poma L, Krzesinski JM, Detry O, Jouret F. Administration of mesenchymal stromal cells before renal ischemia/reperfusion attenuates kidney injury and may modulate renal lipid metabolism in rats. Sci Rep. 2017;7(1):1-13.

DOI: 10.1038/s41598-017-08726-z.

Erpicum P, Detry O, Weekers L, Bonvoisin C, Lechanteur C, Briquet A, et al. Mesenchymal stromal cell therapy in conditions of renal ischaemia/reperfusion. Nephrol Dial Transplant. 2014;29(8):1487-1493.

DOI: org/10.1093/ndt/gft538.

Duffield JS, Park KM, Hsiao LL, Kelley VR, Scadden DT, Ichimura T, et al. Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J Clin Invest. 2005;115(7):1743-1755.

DOI: 10.1172/JCI22593.

Burst VR, Gillis M, Pütsch F, Herzog R, Fischer JH, Heid P, et al. Poor cell survival limits the beneficial impact of mesenchymal stem cell transplantation on acute kidney injury. Nephron Exp Nephrol. 2010;114(3):e107-e116.

DOI: 10.1159/000262318.

Duffield JS, Bonventre JV. Kidney tubular epithelium is restored without replacement with bone marrow-derived cells during repair after ischemic injury. Kidney Int. 2005;68(5):1956-1961.

DOI: 10.1111/j.1523-1755.2005.00629.x.

Humphreys BD. Kidney injury, stem cells and regeneration. Curr Opin Nephrol Hypertens. 2014;23(1):25-31.

DOI: 10.1097/01.mnh.0000437332.31418.e0.

Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10(8):858-864.

DOI: 10.1038/nm1075.

Togel FE, Westenfelder C. Role of SDF-1 as a regulatory chemokine in renal regeneration after acute kidney injury. Kidney Int Suppl. 2011;1(3):87-89.

DOI: 10.1038/kisup.2011.20.

Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, et al. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med. 2008;205(2):479-490.

DOI: 479 10.1084/jem.20071903.

Gheisari Y, Azadmanesh K, Ahmadbeigi N, Nassiri SM, Golestaneh AF, Naderi M, et al. Genetic modification of mesenchymal stem cells to overexpress CXCR4 and CXCR7 does not improve the homing and therapeutic potentials of these cells in experimental acute kidney injury. Stem Cells Dev. 2012;21(16):2969-2980.

DOI: 10.1089/scd.2011.0588.

Heidary Z, Ghaisari J, Moein S, Naderi M, Gheisari Y. Stochastic Petri Net modeling of hypoxia pathway predicts a novel incoherent feed-forward loop controlling SDF-1 Expression in acute kidney injury. IEEE Trans Nanobioscience. 2016;15(1):19-26.

DOI: 10.1109/TNB.2015.2509475.

Chun P. Therapeutic effects of histone deacetylase inhibitors on kidney disease. Arch Pharm Res. 2018;41(2):162-183.

DOI: 10.1007/s12272-017-0998-7.

Brilli LL, Swanhart LM, de Caestecker MP, Hukriede NA. HDAC inhibitors in kidney development and disease. Pediatr Nephrol. 2013;28(10):1909-1921.

DOI: 10.1007/s00467-012-2320-8.

Chen S, El-Dahr SS. Histone deacetylases in kidney development: implications for disease and therapy. Pediatr Nephrol Berl Ger. 2013;28(5):689-698.

DOI: 10.1007/s00467-012-2223-8.

Zacharias N, Sailhamer EA, Li Y, Liu B, Butt MU, Shuja F, et al. Histone deacetylase inhibitors prevent apoptosis following lethal hemorrhagic shock in rodent kidney cells. Resuscitation. 2011;82(1):1-9.

DOI: 10.1016/j.resuscitation.2010.09.469.

Ruiz-Andres O, Suarez-Alvarez B, Sánchez-Ramos C, Monsalve M, Sanchez-Niño MD, Ruiz-Ortega M, et al. The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury. Kidney Int. 2016;89(2):399-410.

DOI: 10.1038/ki.2015.332.

Amirzargar MA, Yaghubi F, Hosseinipanah M, Jafari M, Pourjafar M, Rezaeepoor M, et al. Anti-inflammatory effects of valproic acid in a rat model of renal ischemia/reperfusion injury: alteration in cytokine profile. Inflammation. 2017;40(4):1310-1318.

DOI: 10.1007/s10753-017-0574-9.

Zheng Q, Liu W, Liu Z, Zhao H, Han X, Zhao M. Valproic acid protects septic mice from renal injury by reducing the inflammatory response. J Surg Res. 2014;192(1):163-169.

DOI: 10.1016/j.jss.2014.05.030.

Costalonga EC, Silva FM, Noronha IL. Valproic acid prevents renal dysfunction and inflammation in the ischemia-reperfusion injury model. BioMed Res Int. 2016;2016. ID:5985903. 10 pages.

DOI: 10.1155/2016/5985903.

Speir RW, Stallings JD, Andrews JM, Gelnett MS, Brand TC, Salgar SK. Effects of valproic acid and dexamethasone administration on early bio-markers and gene expression profile in acute kidney ischemia-reperfusion injury in the rat. PloS One. 2015;10(5):1-24.

DOI: 10.1371/journal.pone.0126622.

Chatterjee PK, Brown PA, Cuzzocrea S, Zacharowski K, Stewart KN, Mota-Filipe H, et al. Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. Kidney Int. 2001;59(6):2073-2083.

DOI: 10.1046/j.1523-1755.2001.00722.x.

Wei Q, Dong Z. Mouse model of ischemic acute kidney injury: technical notes and tricks. Am J Physiol Ren Physiol. 2012;303(11):F1487-F1494.

DOI: 10.1152/ajprenal.00352.2012.

Moein S, Javanmard SH, Abedi M, Izadpanahi MH, Gheisari Y. Identification of appropriate housekeeping genes for gene expression analysis in long-term hypoxia-treated kidney cells. Adv Biomed Res. 2017;6:15-28.

DOI: 10.4103/2277-9175.200790.

Wu Y, Tang D, Liu N, Xiong W, Huang H, Li Y, et al. Reciprocal regulation between the circadian clock and hypoxia signaling at the genome level in mammals. Cell Metab. 2017;25(1):73-85.

DOI: 10.1016/j.cmet.2016.09.009.

Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A. 2014;111(45):16219-16224.

DOI: 10.1073/pnas.1408886111.

Costalonga EC, Silva FM, Noronha IL. Valproic acid prevents renal dysfunction and inflammation in the ischemia-reperfusion injury model. BioMed Res Int. 2016;2016:5985903.

DOI: 10.1155/2016/5985903.

Heidari R, Jafari F, Khodaei F, Shirazi Yeganeh B, Niknahad H. Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrol Carlton Vic. 2018;23(4):351-361.

DOI: 10.1111/nep.13012.

Havali C, Gücüyener K, Buyan N, Yılmaz Ü, Gürkaş E, Gülbahar Ö, et al. Does nephrotoxicity exist in pediatric epileptic patients on valproate or carbamazepine therapy? J Child Neurol. 2015;30(3):301-306.

DOI: 10.1177/0883073814538505.

Hamed SA, Rageh TA, Mohamad AO, Abou Elnour SM. Renal dysfunctions/injury in adult epilepsy patients treated with carbamazepine or valproate. Expert Rev Clin Pharmacol. 2018;11(8):819-824.

DOI: 10.1080/17512433.2018.


  • There are currently no refbacks.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.