Histone deacetylase 6 suppression of renal tubular epithelial cell promotes interstitial mineral deposition via alpha-tubulin acetylation

草酸钙 肾皮质 化学 HDAC6型 乙酰化 肾结石 转分化 细胞生物学 细胞 癌症研究 内科学 内分泌学 生物 组蛋白脱乙酰基酶 组蛋白 生物化学 医学 有机化学 基因
作者
Shujue Li,Wenzheng Wu,Baotong Yang,Zezhen Liu,Xiaolu Duan,Xin‐Yuan Sun,Hongxing Liu,Shike Zhang,Yuhao Zhou,Wenqi Wu
出处
期刊:Cellular Signalling [Elsevier BV]
卷期号:116: 111057-111057 被引量:1
标识
DOI:10.1016/j.cellsig.2024.111057
摘要

Randall's plaque (RP) is derived from interstitial mineral deposition and is highly prevalent in renal calcium oxalate (CaOx) stone disease, which is predictive of recurrence. This study shows that histone deacetylase 6 (HDAC6) levels are suppressed in renal tubular epithelial cells in RP samples, in kidney tissues of hyperoxaluria rats, and in hyper-oxalate-treated or mineralized cultured renal tubular epithelial (MDCK) cells in vitro. Mineral deposition in MDCK cells was exacerbated by HDAC6 inhibition but alleviated by HDAC6 overexpression. Surprisingly, the expression of some osteogenic-associated proteins, were not increased along with the increasing of mineral deposition, and result of single-cell RNA sequencing of renal papillae samples revealed that epithelial cells possess lower calcific activity, suggesting that osteogenic-transdifferentiation may not have actually occurred in tubular epithelial cells despite mineral deposition. The initial mineral depositions facilitated by HDAC6 inhibitor were localized in extracellular dome rather than inside the cells, moreover, suppression of HDAC6 significantly increased the calcium content of co-cultured renal interstitial fibroblasts (NRK49F) and enhanced mineral deposition of indirectly co-cultured NRK49F cells, suggesting that HDAC6 may influence trans-MDCK monolayer secretion of mineral. Further experiments revealed that this regulatory role was partially alpha-tubulinLys40 acetylation dependent. Collectively, these results suggest that hyper-oxalate exposure led to HDAC6 suppression in renal tubular epithelial cells, which may contribute to interstitial mineral deposition by promoting alpha-tubulinLys40 acetylation. Therapeutic agents that influence HDAC6 activity may be beneficial in preventing RP and CaOx stone formation.
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