Lack of serum‐ and glucocorticoid‐inducible kinase 3 leads to podocyte dysfunction

Abstract

Serum- and glucocorticoid-inducible kinase 3 (SGK3) is a downstream mediator of PI3K, which is essential for maintaining the functional integrity of podocytes. However, little is known about the role of SGK3 in podocyte function. Herein, we demonstrated that SGK3 contributes to the maintenance of podocyte integrity. Conditionally immortalized mouse podocyte cells (MPCs) were treated with puromycin aminonucleoside (PAN). PAN treatment inhibited the activity of SGK3 and the expression of podocin. Short hairpin RNA (shRNA)-mediated knockdown of SGK3 also reduced podocin expression in the absence of PAN. Adriamycin (ADR)-treated mice developed proteinuria and had decreased renal glomerular SGK3 expression in comparison to control mice. Consistent with a role for SGK3 in the ADR effect, SGK3 knockout (KO) mice had markedly reduced kidney podocin expression and significantly elevated proteinuria compared with wild-type mice. Electron microscopy revealed that SGK3 KO mice displayed partial effacement of podocyte foot processes. Further, a SGK3 target protein, glycogen synthase kinase-3 (GSK3), was discovered to be dramatically activated in PAN and SGK3 shRNA-treated MPCs and in SGK3 KO mice. Taken together, these data strongly suggest that SGK3 plays a significant role in regulating podocyte function, likely by controlling the expression and activity of GSK3.-Peng, L.-Q., Zhao, H., Liu, S., Yuan, Y.-P., Yuan, C.-Y., Mwamunyi, M.-J., Pearce, D., Yao, L.-J. Lack of serum- and glucocorticoid-inducible kinase 3 leads to podocyte dysfunction.

The SGK3-triggered ubiquitin–proteasome degradation of podocalyxin (PC) and ezrin in podocytes was associated with the stability of the PC/ezrin complex

“…As previous studies have shown that ezrin downregulation or the inhibition of PC/ezrin complex activity can lead to podocyte dysfunction 28 – 30 , we first investigated whether the expression levels of PC and ezrin were altered after podocyte damage in an ADR-induced nephritic mouse model, which was established as previously described 4 . By 14 days after ADR injection, ADR-treated mice had developed significant proteinuria in comparison with the control group (Fig.…”

“…We recently reported that SGK3 was involved in the ADR-induced nephritic mouse model and in the PAN-induced podocyte damage cell model 4 . However, it remains unclear whether SGK3 participates in the regulation of PC and ezrin protein expression.…”

“…We previously reported that a lack of serum- and glucocorticoid-inducible kinase 3 (SGK3) resulted in proteinuria in mice and that SGK3 activity and expression were inhibited after podocyte damage, both in vivo and in vitro 4 . 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 .…”

“…AKT2 and SGK3 are fairly homologous in structure and function 11 . Thus it is probable that SGK3 is involved in the pathogenesis of proteinuria after podocyte damage 4 . However, the mechanism by which SGK3 induces podocyte dysfunction remains poorly understood.…”

A frameshift insertion in SGK3 leads to recessive hairlessness in Scottish Deerhounds: a candidate gene for human alopecia conditions

“…Mice with spontaneous and targeted loss-of-function (LoF) variants in Sgk3 have defective hair follicle development and abnormal hair cycle, demonstrating the essential role of the protein in these processes (Masujin et al 2004 ; McCormick et al 2004 ; Alonso et al 2005 ). Sgk3 is quite ubiquitously expressed with proposed roles in other tissues such as in renal function by regulation of podocyte integrity and function (Peng et al 2018 ).…”