Effects of the differential expression of <scp>ZO</scp>‐1 and <scp>ZO</scp>‐2 on podocyte structure and function

<jats:title>Abstract</jats:title><jats:p>Glomerular podocytes in the kidney originate from columnar epithelial cells possessing tight junctions. During podocyte differentiation, tight junctions are replaced by slit diaphragms, which are formed between foot processes and function as a blood filtration barrier. Although the expression of most tight junction components is suppressed during podocyte differentiation, several components, including <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐1 and <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐2, are consistently expressed. We recently showed that podocyte‐specific deletion of <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐1 gene impaired slit diaphragm formation, leading to proteinuria and glomerular sclerosis. Here, we address the relevance of <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐2, whose sequence is highly similar to <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐1, in the maintenance of the structure and function of podocytes. In glomerular development, the spatiotemporal expression of <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐2 was similar to that of <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐1 until the capillary loop stage. Subsequently, the distribution patterns of <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐1 and <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐2 diverged at the maturation stage, when slit diaphragms are formed. This divergence could partly rely on the ability of <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐2 to interact with the slit diaphragm membrane proteins. Podocyte‐specific deletion of the <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐2 gene did not cause overt defects; however, double knockout of <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐1 and <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐2 genes accelerated the defects observed in <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐1 knockout mice. These results suggest that <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐2 plays supportive roles in the <jats:styled-content style="fixed-case">ZO</jats:styled-content>‐1‐dependent regulation of podocyte filtration barrier.</jats:p>