AP-2β/KCTD1 Control Distal Nephron Differentiation and Protect against Renal Fibrosis
AP-2β/KCTD1 Control Distal Nephron Differentiation and Protect against Renal Fibrosis
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DOI：
10.1016/j.devcel.2020.05.026
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发表时间：
2020-08-10
影响因子：
11.8
通讯作者：
Marneros, Alexander G.
中科院分区：
文献类型：
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作者：
Marneros, Alexander G.
协调特定肾单位节段分化的发育机制尚不完全清楚，维持肾发生后终末分化的因素在很大程度上仍然未知。在此，转录因子AP-2 β被证明是肾发生过程中远曲小管前体分化为早期远曲小管（DCT）所必需的。相反，其下游靶点KCTD 1对于早期DCT向成熟DCT的终末分化是必不可少的，并且由于缺乏KCTD 1而导致其终末分化受损导致严重的失盐性肾小管病变。此外，在成人中，持续的KCTD 1活性使成熟的DCT维持在这种终末分化状态，并通过抑制β-连环蛋白活性来防止肾纤维化，而KCTD 1缺乏导致严重的肾纤维化。因此，AP-2 β/KCTD 1轴将肾单位中的发育途径与DCT的终末分化的诱导和维持联系起来，所述终末分化积极地防止它们在成人中的去分化并防止肾纤维化。
The developmental mechanisms that orchestrate differentiation of specific nephron segments are incompletely understood, and the factors that maintain their terminal differentiation after nephrogenesis remain largely unknown. Here, the transcription factor AP-2 beta is shown to be required for the differentiation of distal tubule precursors into early stage distal convoluted tubules (DCTs) during nephrogenesis. In contrast, its downstream target KCTD1 is essential for terminal differentiation of early stage DCTs into mature DCTs, and impairment of their terminal differentiation owing to lack of KCTD1 leads to a severe salt-losing tubulopathy. Moreover, sustained KCTD1 activity in the adult maintains mature DCTs in this terminally differentiated state and prevents renal fibrosis by repressing beta-catenin activity, whereas KCTD1 deficiency leads to severe renal fibrosis. Thus, the AP-2 beta/KCTD1 axis links a developmental pathway in the nephron to the induction and maintenance of terminal differentiation of DCTs that actively prevents their de-differentiation in the adult and protects against renal fibrosis.