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bioRxiv · 10.1101/2023.06.27.546796

Histone deacetylase 3 plays a critical role in hypertension-induced kidney inflammation and fibrosis

An, C.·Jiao, B.·Du, H.·Tran, M.·Song, B.·Wang, P.·Hu, Z.·Zhou, D.·Wang, Y.
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Abstract

Objective: Hypertension is a major cause of chronic kidney disease. The molecular mechanisms how hypertension causes kidney disease are not fully understood. In this study, we examined the functional role of histone deacetylase 3 (HDAC3) in the pathogenesis of hypertensive kidney disease. Approach and Results: Myeloid HDAC3 knockout mice were generated by crossing HDAC3f/f mice with LysM-Cre+/- mice. Both LysM-Cre-/-HDAC3f/f (HDAC3CON) mice and LysM-Cre+/+HDAC3f/f (HDAC3MKO) mice were subjected to uninephrectomy and treated with angiotensin II at 1.5 ug/kg/min or vehicle for 28 days. Blood pressure increased comparably in both HDAC3CON and HDAC3MKO mice following angiotensin II treatment. Compared with HDAC3CON mice, HDAC3MKO mice were protected from angiotensin II-induced kidney dysfunction and pathological injury and developed less proteinuria. Myeloid HDAC3 deficiency markedly attenuated the protein levels of fibronectin, collagen I, and ?-SMA in the kidney following angiotensin II treatment. Furthermore, HDAC3MKO mice accumulated significantly fewer myeloid fibroblasts and macrophages in the kidney after angiotensin II treatment. Myeloid HDAC3 deficiency significantly reduced the mRNA expression of proinflammatory molecules in the kidney following angiotensin II treatment. In cultured macrophages, knockdown of HDAC3 with shRNA suppressed proinflammatory molecule expression. Furthermore, knockdown of HDAC3 inhibited NF-kB p65 enrichment to IL-6 promoter. Conclusion: Our study identifies a critical role of myeloid HDAC3 in the regulation of hypertension-induced kidney inflammation and fibrosis. Targeting HDAC3 may represent a novel therapeutic strategy for hypertensive kidney disease.

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An, C., Jiao, B., Du, H., Tran, M., Song, B., Wang, P., Hu, Z., Zhou, D., Wang, Y.. 2023-06-29. Histone deacetylase 3 plays a critical role in hypertension-induced kidney inflammation and fibrosis. https://doi.org/10.1101/2023.06.27.546796

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