Aims: [Valproic acid](https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=summary&ligandId=7009) is an inhibitor of histone deacetylases (HDACs) and a drug used for the treatment of epileptic seizures. The drug (sodium valproate) has antihypertensive effects and HDACs modulate renal Na +-transporting ATPases. The aim was to investigate whether valproate could be repositioned as an adjunctive drug for the prevention of acute kidney injury (AKI) Methods: AKI due to ischemia followed by reperfusion (I/R) was induced by clamping of the renal arteries (45 min) in rats that had received valproate or vehicle for 20 days. Plasma creatinine and urea concentrations, glomerular filtration rate, plasma and urinary Na + and K + concentrations, urinary excretion of Na + and K +, (Na ++K +)ATPase activity from proximal tubules, and blood pressure were measured 48 h later. Results: The increase in plasma creatinine concentration and its decrease in urine are prevented by valproate. The elevated plasma urea concentration in rats subjected to I/R is also normalized. Urinary excretion of Na + and K + decreases by ~50% in I/R rats, but while the former shows a trend of recovery by valproate, this does not occur with K +. The plasma levels of both ions remain ~10% below those of Sham controls. The decrease in proximal tubule (Na ++K +)ATPase activity in I/R rats is also prevented by valproate. Lastly, the severe arterial hypertension that develops after AKI is completely prevented by valproate. Conclusions: Valproate has pharmacological properties that point to its potential repositioning as an adjuvant in improving several outcomes in AKI and potentially avoiding progression to chronic kidney disease.

Background and Purpose: Acute kidney injury (AKI) is a severe clinical complication with high rates of morbidity and mortality. [Valproic acid](https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=summary&ligandId=7009) is an inhibitor of histone deacetylases (HDACs) and a drug used for the treatment of epileptic seizures. The drug (sodium valproate) has antihypertensive effects and HDACs modulate renal Na +-transporting ATPases. The aim of the present study was to investigate whether valproate could be repositioned as an adjunctive drug for the prevention of AKI. Experimental Approach: AKI due to ischemia followed by reperfusion (I/R) was induced by clamping of the renal arteries (45 min) in rats that had received valproate or vehicle for 20 days from weaning. Plasma creatinine and urea concentrations, glomerular filtration rate, plasma and urinary Na + and K + concentrations, urinary excretion of Na + and K +, (Na ++K +)ATPase activity from proximal tubules, and blood pressure were measured 48 h later. Key Results: The increase in plasma creatinine concentration and its decrease in urine are prevented by valproate. The elevated plasma urea concentration in rats subjected to I/R is also normalized by valproate. Urinary excretion of Na + and K + decreases by ~50% in I/R rats, but while the former shows a trend of recovery by valproate, this does not occur with K +. The plasma levels of both ions remain ~10% below those of Sham controls. The decrease in proximal tubule (Na ++K +)ATPase activity in I/R rats is also prevented by valproate. Lastly, the severe arterial hypertension that develops after AKI due to I/R is completely prevented by the administration of valproate. Conclusions and Implications: Valproate has pharmacological properties that point to its potential repositioning as an adjuvant in improving several outcomes in AKI and potentially avoiding progression to chronic kidney disease.