Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is one of the most common complications associated with diabetes and characterized by renal microvascular injury along with accelerated synthesis of extracellular matrix proteins causing tubulointerstitial fibrosis. Production of type I collagen, the major component of extracellular matrix, is augmented during renal fibrosis after chronic exposure to hyperglycemia. However, the transcriptional modulator responsible for the epigenetic manipulation leading to induction of type I collagen genes is not clearly defined. We show here that tubulointerstitial fibrosis as a result of DN was diminished in myocardin-related transcription factor A (MRTF-A) -deficient mice. In cultured renal tubular epithelial cells and the kidneys of mice with DN, MRTF-A was induced by glucose and synergized with glucose to activate collagen transcription. Notably, MRTF-A silencing led to the disappearance of prominent histone modifications indicative of transcriptional activation, including acetylated histone H3K18/K27 and trimethylated histone H3K4. Detailed analysis revealed that MRTF-A recruited p300, a histone acetyltransferase, and WD repeat-containing protein 5 (WDR5), a key component of the histone H3K4 methyltransferase complex, to the collagen promoters and engaged these proteins in transcriptional activation. Estradiol suppressed collagen production by dampening the expression and binding activity of MRTF-A and interfering with the interaction between p300 and WDR5 in renal epithelial cells. Therefore, targeting the MRTF-A-associated epigenetic machinery might yield interventional strategies against DN-associated renal fibrosis.

Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

“…All these findings suggest that Nox4 protein levels rise under fibrogenic (predominantly diabetic) conditions, and this contributes to the ensuing nephropathy and fibrosis. Consistent with this scenario and our new findings, a recent paper reports that MRTFdeficient mice are largely protected against DKD (16). However, results obtained with whole body Nox4 knock-out mice are controversial or more complex.…”

“…Thus, cytoskeleton remodeling is not only an early feature of the phenotypic shift but also a key driver of the ensuing transcriptional reprogramming, thereby linking cell structure to gene expression via the MRTF/SRF pathway (14). Accordingly, we and others have shown that genetic or pharmacological inhibition of MRTF prevents myofibroblast transition (8,10) and lessens organ fibrosis (15)(16)(17).…”

A crosstalk between chromatin remodeling and histone H3K4 methyltransferase complexes in endothelial cells regulates angiotensin II-induced cardiac hypertrophy

“…Further investigation is warranted to seek a unified model wherein chromatin remodeling and histone modifying proteins cooperate to regulate different pathophysiological events. Finally, our recent findings suggest that MRTF-A regulates cellular fibrogenesis likely through the same set of epigenetic factors as described here [15,16]. Collectively, these data allude to a broad role for MRTF-A in cellular response to injuries signals, which is consistent with a recent paper linking MRTF-A activation to wound healing [43].…”

Histone acetyltransferase p300 promotes MRTF-A-mediates transactivation of VE-cadherin gene in human umbilical vein endothelial cells

“…The regulation of proangiogenic factor cyr61 upon mechanical overload depends on the cooperation of MRTF-A and p300 (Hanna et al, 2009). A recent study also determined that MRTF-A can recruit p300 to the collagen promoters and activate this target gene transcription, thus contributing to the progression of renal fibrosis and diabetic nephropathy (Xu et al, 2014). Using ChIP assay, we observed a clear increase in the acetylation levels of H3K9 H3K14 and H4 at the SRF binding site of the VE-cadherin promote, when HUVECs were overexpressed with MRTF-A.…”