Possible therapeutic repositioning of valproic acid: From epileptic seizures to acute kidney injury

Abstract Aims Valproic acid is an inhibitor of histone deacetylases (HDACs) and is 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 in rats that had received valproate or a vehicle for 20 days. Plasma creatinine and urea concentrations, and glomerular filtration rate (colorimetrically); plasma and urinary Na + and K + concentrations, and urinary excretion of Na + and K + (spectrophotometrically); proximal tubules (Na + +K + )ATPase activity (release of P i from ATP); and blood pressure (pletismography) were measured 48 h later. Results AKI increases plasma creatinine and returns to baseline values observed in non‐operated animals when I/R rats are pretreated with valproate. Its decrease in urine is significantly prevented by valproate administration. The elevated plasma urea concentration is significantly reduced. Urinary excretion of Na + and K + decreases in I/R, but while the former is recovered by valproate, this does not occur with K + . The plasma levels of both ions remain ~10% below those of Sham controls. The decrease in (Na + +K + )ATPase activity in I/R rats is totally prevented by valproate. The AKI‐provoked hypertension is 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.