Claudin-19 定位于粗升肢，其中连接 Claudin-16 定位需要其表达,Annals of the New York Academy of Sciences

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Claudin-19 定位于粗升肢，其中连接 Claudin-16 定位需要其表达
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2023-06-21 , DOI: 10.1111/nyas.15014
Henrik Dimke _{1,

2} , Camille Griveau _{3,

4} , Wung-Man Evelyne Ling _{3,

4} , Gaelle Brideau _{3,

4} , Lydie Cheval _{3,

4} , Pravina Muthan _{3,

4} , Dominik Müller ₅ , Amr Al-Shebel ₅ , Pascal Houillier _{3,

4,

6,

7,

8} , Caroline Prot-Bertoye _{3,

4,

6,

7,

8}

Affiliation

肾脏对于矿物质稳态至关重要。肾粗升肢 (TAL) 中的钙和镁重吸收涉及claudin-16 (CLDN16) 和claudin-19 (CLDN19)，任一基因的致病性变异都会导致家族性低镁血症伴高钙尿症和肾钙质沉着症 (FHHNC) 伴严重的钙和镁消耗。虽然 CLDN16 和 CLDN19 均定位于 TAL，但使用不同的抗体报告了肾小管中不同的表达模式。因此，我们使用三种抗 CLDN19 抗体研究了 CLDN19 在野生型和Cldn19缺失小鼠肾脏中的定位，并检查了Cldn19缺失对 CLDN16 和 CLDN10 定位的作用。我们发现 CLDN19 定位于髓质和皮质 TAL 的基底外侧膜域，但仅定位于外髓质和皮质外条纹中 TAL 的紧密连接处，在此与 CLDN16 共定位。此外，在Cldn19缺失小鼠的 TAL 中，CLDN16 在基底外侧膜域表达，但在紧密连接处不表达。相反，Cldn19消融不会改变 CLDN10 定位。这些发现直接暗示 CLDN19 通过允许 CLDN16 的连接插入来调节 TAL 的通透性，并可能解释 FHHNC 患者共有的肾脏表型特征。

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Claudin-19 localizes to the thick ascending limb where its expression is required for junctional claudin-16 localization

The kidney is critical for mineral homeostasis. Calcium and magnesium reabsorption in the renal thick ascending limb (TAL) involves claudin-16 (CLDN16) and claudin-19 (CLDN19) and pathogenic variants in either gene lead to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) with severe calcium and magnesium wasting. While both CLDN16 and CLDN19 localize to the TAL, varying expression patterns in the renal tubule have been reported using different antibodies. We, therefore, studied the localization of CLDN19 in the kidneys of wild-type and Cldn19-deleted mice using three anti-CLDN19 antibodies and examined the role of Cldn19 deletion on CLDN16 and CLDN10 localization. We find that CLDN19 localizes to basolateral membrane domains of the medullary and cortical TAL but only to the tight junction of TALs in the outer stripe of outer medulla and cortex, where it colocalizes with CLDN16. Furthermore, in TALs from Cldn19-deleted mice, CLDN16 is expressed in basolateral membrane domains but not at the tight junction. In contrast, Cldn19 ablation does not change CLDN10 localization. These findings directly implicate CLDN19 in regulating permeability in the TAL by allowing junctional insertion of CLDN16 and may explain the shared renal phenotypic characteristics in FHHNC patients.

更新日期：2023-06-21

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