Deiodinase-3 is a thyrostat to regulate podocyte homeostasis.
Deiodinase-3 is a thyrostat to regulate podocyte homeostasis.
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DOI：
10.1016/j.ebiom.2021.103617
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发表时间：
2021-10
期刊：
影响因子：
11.1
通讯作者：
Reiser J
中科院分区：
文献类型：
--
作者：
Agarwal S;Koh KH;Tardi NJ;Chen C;Dande RR;WerneckdeCastro JP;Sudhini YR;Luongo C;Salvatore D;Samelko B;Altintas MM;Mangos S;Bianco A;Reiser J
肾病综合征（NS）与肾脏足细胞损伤有关，可能作为甲状腺自身免疫的一部分发生，如Graves病。因此，本研究旨在确定足细胞是否以及如何响应和调节生物活性甲状腺激素（TH），3，5，3 ′-三碘甲状腺原氨酸（T3）的输入;并破译3型脱碘酶（D3），一种膜结合硒酶，失活TH，在肾脏疾病中的病理生理作用。为了研究D3在健康和损伤（PAN，嘌呤霉素氨基糖苷和LPS，脂多糖介导的）足细胞中的功能，使用免疫荧光、qPCR和足细胞特异性D3敲除小鼠。表面等离子体共振（SPR），免疫共沉淀和邻近连接试验（PLA）用于相互作用的研究。健康足细胞表达D3作为主要的脱碘酶亚型。在足细胞损伤后，Dio 3转录物和D3蛋白的水平在体外和足细胞损伤的LPS小鼠模型中都显著降低。D3不再直接定位于细胞膜，而是聚集在高尔基体和细胞核中。此外，从小鼠足细胞中消耗D3导致足突消失和蛋白尿。用T3处理小鼠足细胞表型模拟D3的缺失，并引发αvβ3整合素信号转导的激活，这导致足细胞损伤。我们还证实了小鼠足细胞上存在活性促甲状腺激素受体（TSH-R），其参与和激活导致足细胞损伤。该研究提供了D3-αvβ3整合素相互作用如何最大限度地减少T3依赖性整合素活化的机制，说明了D3如何在足细胞中作为肾保护性甲状腺抑制剂。此外，甲状腺激素受体与甲状腺激素受体抗体结合引起的损伤，如在格雷夫斯病患者中发现的，解释了甲状腺疾病和NS之间的合理联系。这项工作得到了美国甲状腺协会（ATA-2018-050.R1）的支持。
Nephrotic syndrome (NS) is associated with kidney podocyte injury and may occur as part of thyroid autoimmunity such as Graves’ disease. Therefore, the present study was designed to ascertain if and how podocytes respond to and regulate the input of biologically active thyroid hormone (TH), 3,5,3′-triiodothyronine (T3); and also to decipher the pathophysiological role of type 3 deiodinase (D3), a membrane-bound selenoenzyme that inactivates TH, in kidney disease. To study D3 function in healthy and injured (PAN, puromycin aminonucleoside and LPS, Lipopolysaccharide-mediated) podocytes, immunofluorescence, qPCR and podocyte-specific D3 knockout mouse were used. Surface plasmon resonance (SPR), co-immunoprecipitation and Proximity Ligation Assay (PLA) were used for the interaction studies. Healthy podocytes expressed D3 as the predominant deiodinase isoform. Upon podocyte injury, levels of Dio3 transcript and D3 protein were dramatically reduced both in vitro and in the LPS mouse model of podocyte damage. D3 was no longer directed to the cell membrane, it accumulated in the Golgi and nucleus instead. Further, depleting D3 from the mouse podocytes resulted in foot process effacement and proteinuria. Treatment of mouse podocytes with T3 phenocopied the absence of D3 and elicited activation of αvβ3 integrin signaling, which led to podocyte injury. We also confirmed presence of an active thyroid stimulating hormone receptor (TSH-R) on mouse podocytes, engagement and activation of which resulted in podocyte injury. The study provided a mechanistic insight into how D3-αvβ3 integrin interaction can minimize T3-dependent integrin activation, illustrating how D3 could act as a renoprotective thyrostat in podocytes. Further, injury caused by binding of TSH-R with TSH-R antibody, as found in patients with Graves’ disease, explained a plausible link between thyroid disorder and NS. This work was supported by American Thyroid Association (ATA-2018-050.R1).
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影响因子：
82.9
作者：
Hayek SS;Koh KH;Grams ME;Wei C;Ko YA;Li J;Samelko B;Lee H;Dande RR;Lee HW;Hahm E;Peev V;Tracy M;Tardi NJ;Gupta V;Altintas MM;Garborcauskas G;Stojanovic N;Winkler CA;Lipkowitz MS;Tin A;Inker LA;Levey AS;Zeier M;Freedman BI;Kopp JB;Skorecki K;Coresh J;Quyyumi AA;Sever S;Reiser J
通讯作者：
Reiser J
影响因子：
29.4
作者：
Dentice, Monica;Luongo, Cristina;Salvatore, Domenico
通讯作者：
Salvatore, Domenico
影响因子：
4.8
作者：
Boelen, A;Kwakkel, J;Visser, TJ
通讯作者：
Visser, TJ
影响因子：
--
作者：
Basu G;Mohapatra A
通讯作者：
Mohapatra A
影响因子：
3
作者：
Chadha, V;Alon, US
通讯作者：
Alon, US