The structural and functional organization of the podocyte filtration slits is regulated by Tjp1/ZO-1.

Masahiko Itoh,Taiji Matsusaka,Kazuhiko Nakadate,Jianliang Xu,Walter Hunziker,Hiroyuki Sugimoto,Yasuhiro Horibata,Alan S Fanning

doi:10.1371/journal.pone.0106621

Abstract

Blood filtration in the kidney glomerulus is essential for physiological homeostasis. The filtration apparatus of the kidney glomerulus is composed of three distinct components: the fenestrated endothelial cells, the glomerular basement membrane, and interdigitating foot processes of podocytes that form the slit diaphragm. Recent studies have demonstrated that podocytes play a crucial role in blood filtration and in the pathogenesis of proteinuria and glomerular sclerosis; however, the molecular mechanisms that organize the podocyte filtration barrier are not fully understood. In this study, we suggest that tight junction protein 1 (Tjp1 or ZO-1), which is encoded by Tjp1 gene, plays an essential role in establishing the podocyte filtration barrier. The podocyte-specific deletion of Tjp1 down-regulated the expression of podocyte membrane proteins, impaired the interdigitation of the foot processes and the formation of the slit diaphragm, resulting in glomerular dysfunction. We found the possibility that podocyte filtration barrier requires the integration of two independent units, the pre-existing epithelial junction components and the newly synthesized podocyte-specific components, at the final stage in glomerular morphogenesis, for which Tjp1 is indispensable. Together with previous findings that Tjp1 expression was decreased in glomerular diseases in human and animal models, our results indicate that the suppression of Tjp1 could directly aggravate glomerular disorders, highlights Tjp1 as a potential therapeutic target.

Highlights

Renal glomerulus is an indispensable system for ultrafiltration of the blood and ensures that essential plasma proteins are retained
Immunofluorescence analyses revealed that the intensity and staining pattern of either Tjp2 or Tjp3 was not altered in the Nphs1-Cre: Tjp1flox/flox mice (Tjp1gpod) compared with the pattern in the Tjp1flox/flox mice (Fig. S3A and B), suggesting that these molecules could not compensate for the loss of Tjp1 in the podocytes
We noticed that the glomerular basement membrane (GBM) is mostly well-organized with the clear three layers in the Tjp1gpod mice at 2 weeks of age (Fig. S3E), while the organization of GBM is severely impaired at 6 weeks of age (Fig. 1G), suggesting that the loss of slit diaphragms and foot process effacement precede the disorganization of the basement membrane in this mutant mouse

Summary

Introduction

Renal glomerulus is an indispensable system for ultrafiltration of the blood and ensures that essential plasma proteins are retained. Glomerular dysfunction is marked by the loss of protein in the urine or proteinuria, which leads to end-stage renal disease due to sclerosis of the glomerulus [1]. Recent studies have clarified that the loss of function of the components of the glomerular podocyte has been implicated in progressive renal diseases such as diabetic nephropathy and focal segmental glomerulosclerosis (FSGS) [2]. The mice that are deficient for these molecules have exhibited renal diseases; while the age of onset may be varied, indicating that the molecules expressed in the podocytes regulate glomerular functions [7,8,9,10]

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Results

Conclusion