Role of c-Abl and nephrin in podocyte cytoskeletal remodeling induced by angiotensin II

Yiqiong Ma,Qian Yang,Wei Liang,Yingjie Yang,Zhentong Zhong,Guohua Ding,Lu Zhang

doi:10.1038/s41419-017-0225-y

Yiqiong Ma, Qian Yang + Show 5 more

Open Access

https://doi.org/10.1038/s41419-017-0225-y

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Abstract

Our previous study showed that angiotensin II (Ang II) exposure diminished the interaction between nephrin and c-Abl, then c-Abl mediated SHIP2-Akt pathway in the process of podocyte injury in vivo and vitro. However, the relationship between nephrin and c-Abl was unknown. Recently, various studies showed that nephrin was required for cytoskeletal remodeling in glomerular podocytes. But its specific mechanisms remain incompletely understood. As a nonreceptor tyrosine kinase involved in cytoskeletal regulation, c-Abl may be a candidate of signaling proteins interacting with Src homology 2/3 (SH2/SH3) domains of nephrin. Therefore, it is proposed that c-Abl contributes to nephrin-dependent cytoskeletal remodeling of podocytes. Herein, we observed that nephrin-c-Abl colocalization were suppressed in glomeruli of patients with proteinuria. Next, CD16/7-nephrin and c-Abl vectors were constructed to investigate the nephrin-c-Abl signaling pathway in podocyte actin-cytoskeletal remodeling. The disorganized cytoskeleton stimulated by cytochalasin D in COS7 cells was dramatically restored by co-transfection with phosphorylated CD16/7-nephrin and c-Abl full-length constructs. Further, co-immunoprecipitation showed that phosphorylated CD16/7-nephrin interacted with wild-type c-Abl, but not with SH2/SH3-defective c-Abl. These findings suggest that phosphorylated nephrin is able to recruit c-Abl in a SH2/SH3-dependent manner and detached c-Abl from dephosphorylated nephrin contributes to cytoskeletal remodeling in podocytes.

Highlights

Podocytes, which play a key role in maintaining the kidney blood filtration barrier, are unique epithelial cells with a large cell body and long processes[1,2,3]
7 minimal change disease (MCD) patients, 8 focal segmental glomerulosclerosis (FSGS) patients, and 11 membranous nephropathy (MN) patients, were enrolled in this study, and renal biopsies were performed on all the patients
No differences were observed between groups regarding age, gender, or blood pressure (BP) values; urinary albumin and serum creatinine values were higher in the experimental groups than in the control group (Table 1)

Summary

Introduction

Podocytes, which play a key role in maintaining the kidney blood filtration barrier, are unique epithelial cells with a large cell body and long processes[1,2,3]. Microtubules and intermediate filaments form the framework of the podocyte cell body and primary processes, whereas the secondary processes are rich in actin[4]. The complex and unique actin cytoskeleton structure enables podocyte to adapt to fluctuating pressures and potentially harmful molecules contained in the primary filtrate[5,6,7]. Remodeling of the actin cytoskeleton is closely related to foot process effacement, podocyte loss, and proteinuria[1]. The foot processes of neighboring podocytes interdigitate and form a specialized intercellular junction called the slit diaphragm. The transmembrane protein nephrin, a member of the immunoglobulin superfamily, is expressed at the intercellular junction of differentiated podocytes and is of utmost importance in maintaining the integrity of the slit diaphragm[9,10].

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