Metabolically active and polyploid renal tissues rely on graded cytoprotection to drive developmental and homeostatic stress resilience.
Metabolically active and polyploid renal tissues rely on graded cytoprotection to drive developmental and homeostatic stress resilience.
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代谢活性和多倍体肾组织依赖于分级的细胞保护来驱动发育和稳态应激恢复。
DOI：
10.1242/dev.197343
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发表时间：
2021-04-15
期刊：
影响因子：
--
通讯作者：
Weavers H
中科院分区：
文献类型：
--
作者：
Burbridge K;Holcombe J;Weavers H
身体组织经常暴露在压力下，从细胞代谢过程中产生的有毒副产物到感染或受伤。虽然已经确定组织通过快速上调细胞保护机制来响应外源性损伤，但对能量需求组织-易受持续内源性损伤-如何承受应力的了解甚少。在这里，我们表明，细胞保护因子Nrf 2和Gadd 45作用于一个特定的肾细胞亚型，能量和生物合成活性的“主”细胞，在果蝇肾发育和稳态驱动应激恢复。缺乏Gadd 45的肾小管表现出显著的形态发生缺陷（细胞死亡，炎性浸润和倍性降低），并在胚胎后生活中积累显著的DNA损伤。同时，转录因子Nrf 2在强烈的肾生理活动期间是活跃的，在此它保护代谢活跃的肾细胞免受氧化损伤。尽管它的组成性质，肾细胞保护活性必须精确平衡，并在适度的亚损伤水平持续;事实上，进一步的实验海拔显着扰乱肾发育和功能。我们认为，需要长期保护的组织必须采用有限的细胞保护活性，而更高的水平可能只会是有益的，如果激活瞬时先发制人外源性的侮辱。 细胞保护因子Nrf 2和Gadd 45在发育和稳态过程中驱动代谢活跃的果蝇肾细胞对内源性氧化和遗传毒性应激的恢复力，并且在外源性损伤后进一步升高。
Body tissues are frequently exposed to stress, from toxic byproducts generated during cellular metabolism through to infection or wounding. Although it is well-established that tissues respond to exogenous injury by rapidly upregulating cytoprotective machinery, how energetically demanding tissues – vulnerable to persistent endogenous insult – withstand stress is poorly understood. Here, we show that the cytoprotective factors Nrf2 and Gadd45 act within a specific renal cell subtype, the energetically and biosynthetically active ‘principal’ cells, to drive stress resilience during Drosophila renal development and homeostasis. Renal tubules lacking Gadd45 exhibit striking morphogenetic defects (with cell death, inflammatory infiltration and reduced ploidy) and accumulate significant DNA damage in post-embryonic life. In parallel, the transcription factor Nrf2 is active during periods of intense renal physiological activity, where it protects metabolically active renal cells from oxidative damage. Despite its constitutive nature, renal cytoprotective activity must be precisely balanced and sustained at modest sub-injury levels; indeed, further experimental elevation dramatically perturbs renal development and function. We suggest that tissues requiring long-term protection must employ restrained cytoprotective activity, whereas higher levels might only be beneficial if activated transiently pre-emptive to exogenous insult. The cytoprotective factors Nrf2 and Gadd45 drive resilience to endogenous oxidative and genotoxic stress in metabolically-active Drosophila renal cells during development and homeostasis, and are further elevated following exogenous insult.
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DOI：
10.1242/dev.088989
发表时间：
2013-03
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Denholm B;Hu N;Fauquier T;Caubit X;Fasano L;Skaer H
通讯作者：
Skaer H
影响因子：
9
作者：
Bocedi A;Noce A;Rovella V;Marrone G;Cattani G;Iappelli M;De Paolis P;Iaria G;Sforza D;Gallù M;Tisone G;Di Daniele N;Ricci G
通讯作者：
Ricci G
影响因子：
19.6
作者：
Chen, Yung-Hsiang;Liu, Hsin-Ping;Chen, Wen-Chi
通讯作者：
Chen, Wen-Chi
影响因子：
9.2
作者：
Denholm, B;Sudarsan, V;Skaer, H
通讯作者：
Skaer, H
影响因子：
29
作者：
Albrecht, Simone C.;Barata, Ana Gomes;Dick, Tobias P.
通讯作者：
Dick, Tobias P.