Serum and Glucocorticoid-Inducible Kinase 3/Nedd4-2 Signaling Pathway Participates in Podocyte Injury by Regulating the Stability of Nephrin.

Serum and glucocorticoid-inducible kinase 3 (SGK3) is involved in maintaining podocyte function by regulating the protein levels of podocin and CD2-associated protein. Nephrin is also one of the slit diaphragm proteins of podocytes, but whether SGK3 participates in podocyte injury by regulating the levels of nephrin remains unclear. In this study, we focused on whether SGK3 affects nephrin levels and the mechanisms involved in the same. In the kidneys of adriamycin (ADR)-induced podocyte injury mouse model, the protein levels of SGK3 and nephrin were significantly decreased. Furthermore, the expression of SGK3 was negatively correlated with the output of proteinuria, and positively correlated with the levels of nephrin. In ADR-treated conditionally immortalized mouse podocyte cells (MPCs), the protein levels of nephrin and SGK3 were inhibited, while the constitutive expression of SGK3 reversed the ADR-induced decline in nephrin protein levels. Furthermore, ADR treatment or SGK3 inactivation enhanced the ubiquitin-proteasome degradation of nephrin in MPCs, and dramatically activated downstream effector proteins of SGK3, neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2) and glycogen synthase kinase-3 ß (GSK3ß). Similarly, Nedd4-2 or GSK3ß overexpression resulted in increased activity of Nedd4-2 or GSK3ß, and significantly downregulated nephrin levels. Interestingly, ubiquitin-mediated protein degradation of nephrin was regulated by Nedd4-2, rather than by GSK3ß. In summary, SGK3 inactivation downregulated the levels of nephrin by increasing Nedd4-2 and GSK3ß activity in ADR-induced podocyte injury model; in particular, the SGK3/Nedd4-2 signaling pathway was found to be involved in ubiquitin-mediated proteasome degradation of nephrin.

Landscape of immune checkpoint inhibitor-related adverse events in Chinese population.

This study aimed to describe the landscape of Immune checkpoint inhibitors (ICIs)-related adverse events (AEs) in a predominantly Chinese cohort. We searched electronic datasets including PubMed, Web of Science and Embase to identify and recruit relevant trials up to September 2, 2019. Clinical trials focusing on ICIs in Chinese patients or a predominantly Chinese population were included. Incidences of treatment-related AEs (TRAEs) and immune-related AEs (irAEs) were pooled and compared. In total, we recruited 13 trials consisting of 1063 patients, with 922 (86.7%) receiving ICI monotherapy and 141 (13.3%) receiving combination of ICI with chemotherapy or anti-angiogenesis. The pooled incidence of any grade TRAEs, grade 1-2, grade 3-5 TRAEs, any grade irAEs, grade 1-2 irAEs and grade 3-5 irAEs in all 1063 patients were 84.1%, 63.3%, 20.9%, 43.3%, 40.0% and 3.0%, respectively. Moreover, 4.3% (44/1018) of patients experienced treatment discontinuation and only 8 (0.8%) patients experienced treatment-related death. Compared to ICI monotherapy, combination significantly increased grade 3-5 TRAEs (46.1% vs. 17.0%, P < 0.001) and grade 3-5 irAEs (7.1% vs. 2.0%, P = 0.015). By comparing the toxicity profiles between different ICIs, we found some drug-specific AEs such as reactive capillary haemangiomas for camrelizumab (58.6%), hyperglycemia for toripalimab (55.6%) and pyrexia for tislelizumab (54.3%). Additionally, nivolumab has the lowest incidence of any grade (64.1%) and grade 3-5 (11.8%) TRAEs. ICI-related AEs were generally mild and tolerable for a predominantly Chinese cohort. However, we should pay attention to the combination of ICI with chemotherapy as it could increase grade 3-5 TRAEs and irAEs.

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

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.