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Endothelial-derived factors regulate a wide range of pathophysiological events. It has been reported previously that IL-33 promotes acute kidney injury (AKI) in mice although the underlying epigenetic mechanism is unclear. In the present study we investigated the role of BRG1, a chromatin remodeling protein, in AKI with a focus on its regulation of IL-33 expression in endothelial cells. Smarca4 -flox mice were crossbred with Cdh5 -Cre mice to achieve endothelial-specific deletion of BRG1. AKI was induced by unilateral renal ischemia followed by reperfusion. Compared to wild type (WT) littermates, endothelial conditional BRG1 knockout (CKO) mice were protected from ischemia-reperfusion induced AKI as evidenced by decreased plasma creatinine levels, attenuated caste and tubular necrosis, and diminished immune infiltrates. CKO mice also developed less severe renal fibrosis as indicated by expression levels of extracellular matrix proteins, picrosirius red staining of collagenous tissues, and quantification of renal hydroxylproline levels. Of interest, renal expression of IL-33 was down-regulated as result of endothelial BRG1 deficiency. In cultured endothelial cells, BRG1 directly bound to the IL-33 promoter to activate transcription. Endothelial cell-derived conditioned media promoted the synthesis of pro-fibrogenic proteins in renal tubular epithelial cells. Knockdown of either BRG1 or IL-33 in endothelial cells blunted the pro-fibrogenic response in renal tubular epithelial cells. In conclusion, we propose that BRG1 may contribute to ischemia-reperfusion induced renal injury and fibrosis by promoting IL-33 transcription in endothelial cells. • Endothelial BRG1 deletion attenuates renal IR injury in mice. • Endothelial BRG1 deletion attenuates renal fibrosis in mice. • BRG1 activates IL-33 transcription in endothelial cells. • BRG1 regulates renal tubular epithelial cell injury by activating IL-33. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy is a significant contributor to the global pandemic of heart failure. In the present study we investigated the involvement of myocardin-related transcription factor A (MRTF-A), a transcriptional regulator, in this process. Diabetic cardiomyopathy was induced in mice by feeding with a high-fat diet (HFD) or streptozotocin (STZ) injection. We report that MRTF-A was up-regulated in the hearts of mice with diabetic cardiomyopathy. MRTF-A expression was also up-regulated by treatment with palmitate in cultured cardiomyocytes in vitro. Mechanistically, serum response factor (SRF) bound to the MRTF-A gene promoter and activated MRTF-A transcription in response to pro-diabetic stimuli. Knockdown of SRF abrogated MRTF-A induction in cardiomyocytes treated with palmitate. When cardiomyocytes conditional MRTF-A knockout mice (MRTF-A CKO) and wild type (WT) mice were placed on an HFD to induce diabetic cardiomyopathy, it was found that the CKO mice and the WT mice displayed comparable metabolic parameters including body weight, blood insulin concentration, blood cholesterol concentration, and glucose tolerance. However, both systolic and diastolic cardiac function were exacerbated by MRTF-A deletion in the heart. These data suggest that MRTF-A up-regulation might serve as an important compensatory mechanism to safeguard the deterioration of cardiac function during diabetic cardiomyopathy. [Display omitted] [ABSTRACT FROM AUTHOR]