Fibroblast histone deacetylase-1 promotes kidney interstitial fibrosis following ischemia-reperfusion injury.

Abstract

Interstitial fibrosis is a hallmark of chronic kidney disease, and extracellular matrix is secreted by kidney fibroblasts/pericytes that have differentiated into myofibroblasts. Class I histone deacetylases (HDACs) are highly expressed in the nucleus of kidney cells, where they regulate transcription. Class I HDAC inhibitors prevent interstitial fibrosis in preclinical models of acute kidney injury (AKI). In the warm bilateral ischemia-reperfusion injury (IRI) model, HDAC1 was the only class I HDAC with greater protein abundance following IRI, including in interstitial cells. Thus, it was hypothesized that fibroblast/myofibroblast HDAC1 activation is profibrotic.; hemizygous(iFibHDAC1KO) mice and(control) were given tamoxifen to induce Cre activity 3 wk before warm bilateral IRI or sham surgeries (preventative strategy). The severity of AKI was similar at 24 h postsurgery among the IRI mice, but glomerular rate filtration recovered over the 4-wk study. Despite this, only control male IRI mice developed progressive interstitial fibrosis and tubular injury, which was accompanied by increased kidney myofibroblasts. All the female mice were protected from developing fibrosis with this IRI model. Cultured kidney fibroblasts (NRK49F) overexpressing HDAC1 and/or differentiated to myofibroblasts with transforming growth factor-β1 had a significant shift in the cell cycle from G1 to S and G2 phases and increased proliferation. The HDAC1 overexpressing cultured fibroblasts had increased cell cycle/proliferation and proinflammatory transcriptomes. Indeed, control IRI male mice had significantly greater kidney CD3and F4/80immune cells 24 h postinjury compared with iFibHDAC1KO IRI mice. In conclusion, HDAC1 activation in the kidney fibroblast is profibrotic.This study identified kidney fibroblast HDAC1 as being profibrotic following ischemia and reperfusion in male mice. This epigenetic regulator promotes fibroblast/myofibroblast expansion in the kidney and in cultured fibroblasts. Fibroblast HDAC1 activation caused gene expression of proinflammatory cytokine/chemokines, and knocking down fibroblast HDAC1 in vivo was associated with reduced kidney immune cell infiltration. Thus, preventing fibroblast HDAC1 activation before acute kidney injury can slow the development of kidney interstitial fibrosis.