Valproic Acid Prevents Renal Dysfunction and Inflammation in the Ischemia-Reperfusion Injury Model

Abstract

Ischemia-reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI). At present, there are no effective therapies to prevent AKI. The aim of this study was to analyse whether valproic acid (VPA), a histone deacetylase inhibitor with anti-inflammatory properties, prevents renal IRI. Male Wistar rats were divided into three groups: SHAM rats were subjected to a SHAM surgery, IRI rats underwent bilateral renal ischemia for 45 min, and IRI + VPA rats were treated with VPA at 300 mg/kg twice daily 2 days before bilateral IRI. Animals were euthanized at 48 hours after IRI. VPA attenuated renal dysfunction after ischemia, which was characterized by a decrease in BUN (mg/dL), serum creatinine (mg/dL), and FENa (%) in the IRI + VPA group (39 ± 11, 0.5 ± 0.05, and 0.5 ± 0.06, resp.) compared with the IRI group (145 ± 35, 2.7 ± 0.05, and 4.9 ± 1, resp.; p < 0.001). Additionally, significantly lower acute tubular necrosis grade and number of apoptotic cells were found in the IRI + VPA group compared to the IRI group (p < 0.001). Furthermore, VPA treatment reduced inflammatory cellular infiltration and expression of proinflammatory cytokines. These data suggest that VPA prevents the renal dysfunction and inflammation that is associated with renal IRI.

Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor

“…VPA was found to attenuate the effects of NM on cellular proliferation and oxidative stress. This is consistent with the observation that VPA exerts antioxidant and antiproliferative activity in experimental models of lung injury induced by hyperoxia and ischemia-reperfusion (Cetinkaya, et al, 2015;Costalonga et al, 2016;Wu et al, 2015). VPA has been reported to modulate the expression of genes associated with cell cycle arrest, apoptosis, and DNA repair, as well as oxidative stress (Rucker et al, 2016;Strzalka and Ziemienowicz, 2011); this may contribute to its suppressive effects on NM-induced PCNA and antioxidant expression in the lung.…”

Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus

“…However, the results presented in this paper describe this effect for the first time using an in vitro infection model with DENV, opening an approach for the development of pharmacological treatments using HDAC inhibitors against DENV-induced disease. In this sense, the first candidate for inclusion in future clinical trials could be valproic acid, a well-characterized drug that has been credited with the ability to inhibit HDAC activity and has been used in the study of therapeutic alternatives for the treatment of inflammatory diseases [ 21 , 22 , 23 ].…”

Anti-fibrotic effects of valproic acid in experimental peritoneal fibrosis

“…To investigate the role of histone deacetylase blockade in peritoneal fibrosis, valproic acid (VPA; Depakene, Abbott, Illinois, USA) was administered daily at a dose of 300 mg/kg body weight for 15 days by gavage . The doses of VPA were selected based on previous studies [ 22 , 24 , 25 ].…”

“…By different mechanisms such as reducing macrophage (MΦ) infiltration, and attenuating the expression of TGF-β, VPA has been shown to inhibit fibrosis in liver [ 20 ], kidney [ 12 ], and heart [ 21 ] experimental models. Furthermore, VPA treatment reduced inflammatory cellular infiltration and expression of proinflammatory cytokines, preventing ischemic acute kidney injury in rats [ 22 ]. We therefore hypothesized that VPA could inhibit peritoneal fibrosis (PF).…”