Effects of the differential expression of ZO-1 and ZO-2 on podocyte structure and function.

Abstract

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 ZO-1 and ZO-2, are consistently expressed. We recently showed that podocyte-specific deletion of ZO-1 gene impaired slit diaphragm formation, leading to proteinuria and glomerular sclerosis. Here, we address the relevance of ZO-2, whose sequence is highly similar to ZO-1, in the maintenance of the structure and function of podocytes. In glomerular development, the spatiotemporal expression of ZO-2 was similar to that of ZO-1 until the capillary loop stage. Subsequently, the distribution patterns of ZO-1 and ZO-2 diverged at the maturation stage, when slit diaphragms are formed. This divergence could partly rely on the ability of ZO-2 to interact with the slit diaphragm membrane proteins. Podocyte-specific deletion of the ZO-2 gene did not cause overt defects; however, double knockout of ZO-1 and ZO-2 genes accelerated the defects observed in ZO-1 knockout mice. These results suggest that ZO-2 plays supportive roles in the ZO-1-dependent regulation of podocyte filtration barrier.