γδT Cells Exacerbate Podocyte Injury via the CD28/B7-1-Phosphor-SRC Kinase Pathway

Wanbing Chen,Gaofu Zhang,Haiping Yang,Qiu Li,Mo Wang,You Wu

doi:10.1155/2018/5647120

Abstract

Primary nephrotic syndrome (PNS) is a devastating pediatric disorder. However, its mechanism remains unclear. Previous studies detected B7-1 in podocytes; meanwhile, γδT cells play pivotal roles in immune diseases. Therefore, this study aimed to assess whether and how γδT cells impact podocytes via the CD28/B7-1 pathway. WT and TCRδ−/− mice were assessed. LPS was used to induce nephropathy. Total γδT and CD28+γδT cells were quantitated in mouse spleen and kidney samples. B7-1 and phosphor-SRC levels in the kidney were detected as well. In vitro, γδT cells from the mouse spleen were cocultured with mouse podocytes, and apoptosis rate and phosphor-SRC expression in podocytes were assessed. Compared with control mice, WT mice with LPS nephropathy showed increased amounts of γδT cells in the kidney. Kidney injury was alleviated in TCRδ−/− mice. Meanwhile, B7-1 and phosphor-SRC levels were increased in the kidney from WT mice with LPS nephropathy. CD28+γδT cells were decreased, indicating CD28 may play a role in LPS nephropathy. Immunofluorescence colocalization analysis revealed a tight association of γδT cells with B7-1 in the kidney. High B7-1 expression was detected in podocytes treated with LPS. Podocytes cocultured with γδT cells showed higher phosphor-SRC and apoptosis rate than other cell groups. Furthermore, CD28/B7-1 blockage with CTLA4-Ig in vitro relieved podocyte injury. γδT cells exacerbate podocyte injury via CD28/B7-1 signaling, with downstream involvement of phosphor-SRC. The CD28/B7-1 blocker CTLA4-Ig prevented progressive podocyte injury, providing a potential therapeutic tool for PNS.

Highlights

Primary nephrotic syndrome (PNS), characterized by proteinuria, hypoalbuminemia, hyperlipidemia, and edema, has become a devastating disorder in children
PNS can be divided into minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), mesangial proliferative glomerulonephritis (MPGN), and membranous nephropathy (MGN)
The findings indicated that LPS nephropathy simulates MCD

Summary

Introduction

Primary nephrotic syndrome (PNS), characterized by proteinuria, hypoalbuminemia, hyperlipidemia, and edema, has become a devastating disorder in children. PNS can be divided into minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), mesangial proliferative glomerulonephritis (MPGN), and membranous nephropathy (MGN). MCD accounts for nearly 80% of pediatric cases. Most children with MCD respond well to corticosteroid treatment, but relapse and corticosteroid resistance still constitute important clinical challenges. In 1974, Shalhoub proposed that T cell dysfunction could be the mechanism underlying nephrosis [1]. Subsets of altered CD4+T cells have been reported in PNS patients. We found Th17/Treg subset dysfunction in pediatric PNS [2]. This phenomenon cannot totally explain the mechanism of PNS, especially in its early phase.

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