Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-β1-induced renal injury

Abstract

Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associated with diabetic nephropathy. Histone deacetylase (HDAC) determines the acetylation status of histones and thereby controls the regulation of gene expression. This study examined the effect of HDAC inhibition on renal fibrosis induced by diabetes or transforming growth factor (TGF)-beta1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF-beta1-treated normal rat kidney tubular epithelial cells (NRK52-E), we found that trichostatin A, a nonselective HDAC inhibitor, decreased mRNA and protein expressions of ECM components and prevented EMT. Valproic acid and class I-selective HDAC inhibitor SK-7041 also showed similar effects in NRK52-E cells. Among the six HDACs tested (HDAC-1 through -5 and HDAC-8), HDAC-2 activity significantly increased in the kidneys of STZ-induced diabetic rats and db/db mice and TGF-beta1-treated NRK52-E cells. Levels of mRNA expression of fibronectin and alpha-smooth muscle actin were decreased, whereas E-cadherin mRNA was increased when HDAC-2 was knocked down using RNA interference in NRK52-E cells. Interestingly, hydrogen peroxide increased HDAC-2 activity, and the treatment with an antioxidant, N-acetylcysteine, almost completely reduced TGF-beta1-induced activation of HDAC-2. These findings suggest that HDAC-2 plays an important role in the development of ECM accumulation and EMT in diabetic kidney and that ROS mediate TGF-beta1-induced activation of HDAC-2.

Embryonic Life of Hdac Inhibitors: – In Diabetic Nephropathy

“…[40] HDAC 2 PLAYS IMPORTANT ROLE IN DN [10] Among the six HDACs tested (HDAC-1 through -5 and HDAC-8), HDAC-2 activity significantly amplified in the kidneys of STZ-induced diabetic rats and db/db mice and TGF-β1-treated NRK52-E cells.…”

“…[13] Trichostatin A, a nonselective HDAC inhibitor, reduced mRNA and protein expressions of ECM modules and prevented EMT. [10] IV] CURCUMIN [18] Increased levels of HSP-27 and MAP kinase (p38) in diabetic kidney. However, curcumin treatment prevented this increase in HSP-27 and p38 expression.…”

“…[2] 2. Many isoform of HDAC are up-regulated in diabetic Nephropathy, many study suggest HDAC 2/4/ 9 [10,11,43] plays important role in development of diabetic nephropathy which makes more difficult in interpretation and coming to conclusion which isoform should be targeted in vivo study.…”

“…Although crucial signal transduction and gene regulation mechanisms have been known, especially those associated with effects of hyperglycaemia, transforming growth factor β1 and angiotensin II, progress in efficient genomics, high-throughput sequencing technology, epigenetics and systems biology tactics have greatly extended our understanding and exposed new molecular mechanisms and factors tangled in DN [1] Histone units [30] Gene transcription in eukaryotic cells is strongly responsible by the manner in which DNA is packaged. [10] Each histone is organized into compressed core of the nucleosome and an unstructured Nterminal tail, which extends outside the core. [27] Specific amino acids inside histone tails are targets of many number of post-translational alterations with acetylation, phosphorylation, methylation, and ubiquitination, all of which are tangled in gene-specific transcriptional regulation.…”

Epigenetic Diabetic Vascular Complications

“…In addition, PARP and NF-γB signaling was performed by p300 pathways in diabetic retina, kidney and heart, and led to extracellular matrix (ECM) components augmentation resulting in DVC (37)(38)(39)(40)(41)(42). Research in epigenetic showed that HDACs play a crucial role in TGF-β1-mediated ECM generation and renal parenchymal fibrosis (43)(44)(45). While, lysine acetylation is a temporary histone modification, it is presumably that histone methylation can be more constant and can play pivotal roles in diabetes vascular complications.…”