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HDAC6-mediated ?-tubulin deacetylation suppresses autophagy and enhances motility of podocytes in diabetic nephropathy.


ABSTRACT: Histone deacetylase 6 (HDAC6) is the specific subtype of HDACs which preferentially located in the cytoplasm, and is crucial in insulin signalling. However, the role of HDAC6 in type 2 diabetic nephropathy (DN) remains undefined. In current study, we observed that HDAC6 was markedly activated in the kidneys of type 2 diabetic patients and db/db mice with albuminuria, along with the advanced glycation end products (AGE)-treated podocytes. Selective inhibition of HDAC6 activity protected kidneys from hyperglycaemia in db/db mice. Notably, overexpressing HDAC6 inhibited autophagy and promoted motility aside from the apoptosis of podocytes exposed to AGE. We further determined that HDAC6 regulated the autophagy partially by decreasing the acetylation of ?-tubulin at the residue of lysine 40. In contrast, we confirmed that there was no interaction of HDAC6 with ?-tubulin at the sites of lysine 112 and lysine 352. Consistently, inhibiting HDAC6 by siRNA or the selective inhibitor, tubacin, restored the autophagy level and motility of podocytes and rescued podocytes from AGE stimulation. We provide strong evidence of an unexpected role of HDAC6 in the cascade that modulates podocytes autophagy and motility, enlightening that HDAC6 may be a promising therapeutic target for DN treatment.

SUBMITTER: Liang T 

PROVIDER: S-EPMC7576268 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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HDAC6-mediated α-tubulin deacetylation suppresses autophagy and enhances motility of podocytes in diabetic nephropathy.

Liang Tiantian T   Qi Chunfang C   Lai Yuxiong Y   Xie Jianteng J   Wang Huizhen H   Zhang Li L   Lin Ting T   Jv Menglei M   Li Jing J   Wang Yanhui Y   Zhang Yifan Y   Chen Zujiao Z   Qiu Xueqian X   Li Ruizhao R   Li Zhilian Z   Ye Zhiming Z   Liu Shuangxin S   Liang Xinling X   Shi Wei W   Wang Wenjian W  

Journal of cellular and molecular medicine 20200904 19


Histone deacetylase 6 (HDAC6) is the specific subtype of HDACs which preferentially located in the cytoplasm, and is crucial in insulin signalling. However, the role of HDAC6 in type 2 diabetic nephropathy (DN) remains undefined. In current study, we observed that HDAC6 was markedly activated in the kidneys of type 2 diabetic patients and db/db mice with albuminuria, along with the advanced glycation end products (AGE)-treated podocytes. Selective inhibition of HDAC6 activity protected kidneys f  ...[more]

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