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 pre-clinical 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. Hdac1 flox/flox ; hemizygous Col1a2-cre/ERT (iFibHDAC1KO) mice and Hdac1 flox/flox (control) were given tamoxifen to induce cre activity 3 weeks prior to warm bilateral IRI or sham surgeries (preventative strategy). The severity of AKI was similar at 24 h post-surgery among the IRI mice, but glomerular rate filtration recovered over the 4-week 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 pro-inflammatory transcriptomes. Indeed, control IRI male mice had significantly greater kidney CD3+ and F4/80+ immune cells 24 hours post injury compared to iFibHDAC1KO IRI mice. In conclusion, HDAC1 activation in the kidney fibroblast is profibrotic.
Nguyen et al. (2026) studied this question.