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

Dong, Qing-Qing; Li, Zi-Fang; Zhang, Hui; Shu, Hua-Pan; Tu, Yu-Chi; Liao, Qian-Qian; Yao, Lei

doi:10.3389/fphys.2021.810473

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…It has been reported that the inhibition of SGK1 can exacerbate the proinflammatory ability of microglia and negatively regulate TLR-induced inflammation (Zhou et al, 2015;Inoue et al, 2016). Additionally, our previous studies confirmed that SGK3 deletion could cause podocyte damage and increase proteinuria in mice (Dong et al, 2021). However, whether SGK3 is closely relevant to TECs and immune cells has not yet been explored.…”

Section: Introductionmentioning

confidence: 71%

The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease

et al. 2023

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Introduction: Profibrotic phenotype of renal tubular epithelial cells (TECs) featured with epithelial to mesenchymal transition (EMT) and profibrotic factors secretion, and aberrant accumulation of CD206+ M2 macrophages are the key points in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Nevertheless, the underlying mechanisms involved remain incompletely understood. Serum and glucocorticoid-inducible kinase (SGK) is a serine/threonine protein kinase, required for intestinal nutrient transport and ion channels modulation. T-LAK-cell-originated protein kinase (TOPK) is a member of the mitogen activated protein kinase family, linked to cell cycle regulation. However, little is known about their roles in AKI-CKD transition.Methods: In this study, three models were constructed in C57BL/6 mice: low dose and multiple intraperitoneal injection of cisplatin, 5/6 nephrectomy and unilateral ureteral obstruction model. Rat renal tubular epithelial cells (NRK-52E) were dealt with cisplatin to induce profibrotic phenotype, while a mouse monocytic cell line (RAW264.7) were cultured with cisplatin or TGF-β1 to induce M1 or M2 macrophage polarization respectively. And co-cultured NRK-52E and RAW264.7 through transwell plate to explore the interaction between them. The expression of SGK3 and TOPK phosphorylation were detected by immunohistochemistry, immunofluorescence and western blot analysis.Results:In vivo, the expression of SGK3 and p-TOPK were gradually inhibited in TECs, but enhanced in CD206+ M2 macrophages. In vitro, SGK3 inhibition aggravated epithelial to mesenchymal transition through reducing the phosphorylation state of TOPK, and controlling TGF-β1 synthesis and secretion in TECs. However, SGK3/TOPK axis activation promoted CD206+ M2 macrophage polarization, which caused kidney fibrosis by mediating macrophage to myofibroblast transition (MMT). When co-cultured, the TGF-β1 from profibrotic TECs evoked CD206+ M2 macrophage polarization and MMT, which could be attenuated by SGK3/TOPK axis inhibition in macrophages. Conversely, SGK3/TOPK signaling pathway activation in TECs could reverse CD206+ M2 macrophages aggravated EMT.Discussion: We revealed for the first time that SGK3 regulated TOPK phosphorylation to mediate TECs profibrotic phenotype, macrophage plasticity and the crosstalk between TECs and macrophages during AKI-CKD transition. Our results demonstrated the inverse effect of SGK3/TOPK signaling pathway in profibrotic TECs and CD206+ M2 macrophages polarization during the AKI-CKD transition.

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Section: Introductionmentioning

confidence: 71%

The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease

et al. 2023

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“…We previously reported that the SGK3/Nedd4-2 signaling pathway is involved in the pathogenesis of CKD by regulating the degradation of nephrin and ezrin through ubiquitin-proteasome-mediated protein degradation 32 . To explore how SGK3 specifically regulates the degradation of Pit-1.…”

Section: Resultsmentioning

confidence: 99%

SGK3 promotes vascular calcification via Pit-1 in chronic kidney disease

Dong,

Tu,

Gao

et al. 2024

Theranostics

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Rationale: Vascular calcification (VC) is a life-threatening complication in patients with chronic kidney disease (CKD) caused mainly by hyperphosphatemia. However, the regulation of VC remains unclear despite extensive research. Although serum- and glucocorticoid-induced kinase 3 (SGK3) regulate the sodium-dependent phosphate cotransporters in the intestine and kidney, its effect on VC in CKD remains unknown. Additionally, type III sodium-dependent phosphate cotransporter-1 (Pit-1) plays a significant role in VC development induced by high phosphate in vascular smooth muscle cells (VSMCs). However, it remains unclear whether SGK3 regulates Pit-1 and how exactly SGK3 promotes VC in CKD via Pit-1 at the molecular level. Thus, we investigated the role of SGK3 in the certified outflow vein of arteriovenous fistulas (AVF) and aortas of uremic mice. Methods and Results: In our study, using uremic mice, we observed a significant upregulation of SGK3 and calcium deposition in certified outflow veins of the AVF and aortas, and the increase expression of SGK3 was positively correlated with calcium deposition in uremic aortas. In vitro , the downregulation of SGK3 reversed VSMCs calcification and phenotype switching induced by high phosphate. Mechanistically, SGK3 activation enhanced the mRNA transcription of Pit-1 through NF-κB, downregulated the ubiquitin-proteasome mediated degradation of Pit-1 via inhibiting the activity of neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2), an E3 ubiquitin ligase. Moreover, under high phosphate stimulation, the enhanced phosphate uptake induced by SGK3 activation was independent of the increased protein expression of Pit-1. Our co-immunoprecipitation and in vitro kinase assays confirmed that SGK3 interacts with Pit-1 through Thr468 in loop7, leading to enhanced phosphate uptake. Conclusion: Thus, it is justifiable to conclude that SGK3 promotes VC in CKD by enhancing the expression and activities of Pit-1, which indicate that SGK3 could be a therapeutic target for VC in CKD.

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“…CXCL1 is an NF-κB-dependent potent neutrophil chemoattractant that was found to be expressed in Actn4 KO podocytes and upregulated in FSGS kidney biopsies 35 . Among the most downregulated genes, the E3-ubiquitin ligase NEDD4 was recently found to be involved in ubiquitin-mediated proteasomal degradation of nephrin 36 . Therefore, this downregulation might represent an attempt to stabilize nephrin under stress.…”

Section: Discussionmentioning

confidence: 99%

The podocytes’ inflammatory responses in experimental GN are independent of canonical MYD88-dependent toll-like receptor signaling

Schömig,

Diefenhardt,

Plagmann

et al. 2024

Sci Rep

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Podocytes form the kidney filtration barrier and continuously adjust to external stimuli to preserve their integrity even in the presence of inflammation. It was suggested that canonical toll-like receptor signaling, mediated by the adaptor protein MYD88, plays a crucial role in initiating inflammatory responses in glomerulonephritis (GN). We explored the influence of podocyte-intrinsic MYD88 by challenging wild-type (WT) and podocyte-specific Myd88 knockout (MyD88pko) mice, with a model of experimental GN (nephrotoxic nephritis, NTN). Next-generation sequencing revealed a robust upregulation of inflammatory pathways and changes in cytoskeletal and cell adhesion proteins in sorted podocytes from WT mice during disease. Unchallenged MyD88pko mice were healthy and showed no proteinuria, normal kidney function and lacked morphological changes. During NTN, MyD88pko exhibited a transient increase in proteinuria in comparison to littermates, while histological damage, podocyte ultrastructure in STED imaging and frequencies of infiltrating immune cells by flow cytometry were unchanged. MYD88-deficiency led to subtle changes in the podocyte transcriptome, without a significant impact on the overall podocyte response to inflammation, presumably through MYD88-independent signaling pathways. In conclusion, our study reveals a comprehensive analysis of podocyte adaptation to an inflammatory environment on the transcriptome level, while MYD88-deficiency had only limited impact on the course of GN suggesting additional signaling through MYD88-independent signaling.

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

Cited by 3 publications

References 44 publications

The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease

The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease

SGK3 promotes vascular calcification via Pit-1 in chronic kidney disease

The podocytes’ inflammatory responses in experimental GN are independent of canonical MYD88-dependent toll-like receptor signaling

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