Valproic Acid Attenuates Proteinuria and Kidney Injury

Abstract

Inhibitors of histone deacetylase (HDAC) have anti-inflammatory and antifibrotic effects in several organs and tissues, but their effect on the progression of renal disease is unknown. Here, we studied the effect of valproic acid in adriamycin-induced nephropathy in mice. Administration of valproic acid before kidney injury prevented the development of proteinuria and the onset of glomerulosclerosis. Even after postponing treatment until the peak of adriamycin-induced proteinuria, valproic acid rapidly decreased the quantity of proteinuria and attenuated the progression of renal disease. Valproic acid abrogated the decrease in glomerular acetylation observed during adriamycin-induced nephropathy. Furthermore, valproic acid attenuated the significant upregulation of profibrotic and proinflammatory genes, the deposition of collagen, and the infiltration of macrophages into the kidney. Valproic acid decreased glomerular apoptosis and proliferation induced by adriamycin. Ultrastructural studies further supported the protective effect of valproic acid on podocytes in this model. Taken together, these data suggest that HDACs contribute to the pathogenesis of renal disease and that HDAC inhibitors may have therapeutic potential in CKD.

Histone Deacetylase Inhibitor Enhances Recovery after AKI

“…[35][36][37][38] The mechanism is uncertain; however, it has been shown that epigenetic changes in interstitial fibroblasts obtained from fibrotic kidneys promote fibroblast activation that can be reversed using DNA methyltransferase inhibitors. 39 Because there is extensive crosstalk between histone modification and DNA methylation, 40 it is possible that histone hyperacetylation induced by m4PTB decreases fibrosis by reprogramming these fibroblasts.…”

CoCl₂ Decreases EC-SOD Expression through Histone Deacetylation in COS7 Cells

“…14) Recent studies reported that epigenetics, such as DNA methylation and histone modifications, play pivotal roles in the progression of CKD, and some inhibitors of histone deacetylase (HDAC) exert beneficial effects against CKD. [15][16][17] Moreover, the expression of EC-SOD is known to be regulated by epigenetics in human lung cancer cells, 18,19) monocytes/macrophages, 20) and retina endothelial cells 21) ; however, limited information is currently available on EC-SOD regulation mechanisms in CKD models and the involvement of epigenetics.…”

Isoform-Selective HDAC Inhibition in Autoimmune DiseaseNicole L Regna1* and Christopher M Reilly2

“…The mechanism of action for VPA in the treatment of autoimmune diseases has yet to be identified. However, treatment of ADR nephropathy with VPA was found to increase glomerular H3K9 acetylation and decrease glomerular apoptosis [78].…”

“…Furthermore, treatment of glomerulosclerosis in the adriamycin nephropathy mouse model with VPA reduced proteinuria in early phase renal disease [78]. VPA has been demonstrated to inhibit TNF-α, NF-κB, and IL-6 pathways, which have been shown to be dysregulated during many autoimmune diseases [78].…”

“…VPA has been demonstrated to inhibit TNF-α, NF-κB, and IL-6 pathways, which have been shown to be dysregulated during many autoimmune diseases [78]. The mechanism of action for VPA in the treatment of autoimmune diseases has yet to be identified.…”