Abstract
Podocyte damage is commonly accompanied by destabilization of the podocalyxin (PC)/ezrin complex. Serum- and glucocorticoid-inducible kinase 3 (SGK3) plays a role in the maintenance of podocyte function, but the details of this role are poorly understood. Herein we demonstrated that SGK3 and its downstream target protein neural precursor cell expressed developmentally downregulated protein 4 subtype 2 (Nedd4-2) triggered PC and ezrin interaction. In adriamycin (ADR)-induced nephritic mice, and after puromycin aminonucleoside (PAN)-induced podocyte damage in vitro, PC and ezrin protein expression levels decreased significantly, while Nedd4-2 activity increased. Moreover, PAN treatment increased PC and ezrin ubiquitination and decreased PC/ezrin interaction in cultured mouse podocytes. The downregulation of SGK3 activity in mouse podocytes resulted in decreased PC and ezrin protein expression and increased the ubiquitin–proteasome degradation of PC and ezrin. Furthermore, upregulation of SGK3 activity mostly reversed the PAN-induced decrease in PC and ezrin protein expression. Overexpression of Nedd4-2 led to decreased ezrin protein expression via the upregulation of ezrin ubiquitination. In contrast, Nedd4-2 knockdown resulted in increased ezrin protein expression but decreased ezrin ubiquitination. In PC-transfected human embryonic kidney (HEK293T) cells, SGK3 activity downregulation and Nedd4-2 overexpression resulted in decreased PC/ezrin interaction. These results suggested that SGK3 triggers the ubiquitin–proteasome degradation of PC and ezrin, while the SGK3/Nedd4-2 signaling pathway regulates ezrin, but not PC, ubiquitination. Thus SGK3 helps to regulate podocyte function by maintaining the stability of the PC/ezrin complex.
Highlights
Proteinuria, an important clinical manifestation of chronic kidney disease (CKD), may be caused by the loss of podocyte structural protein function[1,2,3], leading to glomerular sclerosis and end-stage renal failure
We previously reported that a lack of serum- and glucocorticoid-inducible kinase 3 (SGK3) resulted in proteinuria in mice and that Serum- and glucocorticoid-inducible kinase 3 (SGK3) activity and expression were inhibited after podocyte damage, both in vivo and in vitro[4]
These injuries were characterized by glomerular sclerotic lesions and by a tubular dilation with an expanded lumen loaded with proteins (Fig. 1b)
Summary
Proteinuria, an important clinical manifestation of chronic kidney disease (CKD), may be caused by the loss of podocyte structural protein function[1,2,3], leading to glomerular sclerosis and end-stage renal failure. Other studies have shown that the downstream target protein of SGK3, glycogen synthase kinase-3 (GSK3), is involved in the regulation of podocytosis, proteinuria, and podocyte autonomic injury[5,6]. B), SGK3 is a member of the serine–threonine protein kinase family and is highly expressed in mammalian kidney tissue[7]. Extensive studies have shown that AKT2 regulates the survival and function of podocytes during CKD8–10. AKT2 and SGK3 are fairly homologous in structure and function[11]. The mechanism by which SGK3 induces podocyte dysfunction remains poorly understood
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