Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis

Abstract

Histone deacetylases (HDACs) have been shown to alleviate renal fibrosis, however, the role of individual HDAC isoforms in this process is poorly understood. In this study, we examined the role of HDAC8 in the development of renal fibrosis and partial epithelial‐mesenchymal transitions (EMT). In a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), HDAC8 was primarily expressed in renal tubular epithelial cells and time‐dependently upregulated. This occurred in parallel with the deacetylation of cortactin, a nonhistone substrate of HDAC8, and increased expression of three fibrotic markers: α‐smooth muscle actin, collagen 1, and fibronectin. Administration of PCI34051, a highly selective inhibitor of HDAC8, restored acetylation of contactin and reduced expression of those proteins. PCI34051 treatment also reduced the number of renal tubular epithelial cells arrested at the G2/M phase of the cell cycle and suppressed phosphorylation of Smad3, STAT3, β‐catenin, and expression of Snail after ureteral obstruction. In contrast, HDAC8 inhibition reversed UUO‐induced downregulation of BMP7 and Klotho, two renoprotective proteins. In cultured murine proximal tubular cells, treatment with PCI34051 or specific HDAC8 siRNA was also effective in inhibiting transforming growth factor β1 (TGFβ1)‐induced deacetylation of contactin, EMT, phosphorylation of Smad3, STAT3, and β‐catenin, upregulation of Snail, and downregulation of BMP7 and Klotho. Collectively, these results suggest that HDAC8 activation is required for the EMT and renal fibrogenesis by activation of multiple profibrotic signaling and transcription factors, and suppression of antifibrotic proteins. Therefore, targeting HDAC8 may be novel therapeutic approach for treatment of renal fibrosis.

Snai1-induced partial epithelial–mesenchymal transition orchestrates p53–p21-mediated G2/M arrest in the progression of renal fibrosis via NF-κB-mediated inflammation

“…As our understanding toward the mechanisms of renal fibrosis getting increasingly profound, most of the studies have reached the consensus that the maladaptive repair mechanism of TECs plays an important role in the development of renal fibrosis 4,5 . Multiple studies have pointed out the importance of partial EMT and cell cycle arrest during this process 8,11,26 . However, most of the them deemed partial EMT and cell cycle arrest as two separate biological process, and failed to investigate the underlying contact.…”

Epigenetic Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

“…In vivo gene silencing of HDAC4 ameliorated renal injury in STZ-induced diabetic rats, as evidenced by reduced albuminuria, ameliorated podocyte injury and mesangial expansion. 113 Hence, HDAC4 plays a critical role in regulating the pathogenesis of DKD as an epigenetic mediator. Cultured murine proximal tubular cells treated with TGF-β1 also showed protective effects through treatment with PCI34051 (a highly selective inhibitor of HDAC8) or HDAC8 siRNA, suppressing EMT.…”

Indole-Based Small Molecules as Potential Therapeutic Agents for the Treatment of Fibrosis

“…In UUO-induced renal fibrosis mice model, the HDAC8 inhibitor, PCI34051, inhibited Smad3, STAT3, β-catenin and Snail expressions and activated BMP7 and Klotho renal protective protein expressions. In addition, fibrotic markers, including α-SMA, collagen 1, and fibronectin, could be inhibited, thereby alleviating the occurrence of renal fibrosis ( Zhang et al, 2020c ). SB-216763, as a GSK-3β inhibitor, could reverse the hypertrophy and dysfunction of the heart and kidneys in aldosterone (Aldo)-induced rats by suppressing the expression of inflammatory factors including TNF-a, IL-1β, and MCP-1.…”