MAGI-2 scaffold protein is critical for kidney barrier function

Balbas, Minna; Burgess, Michael R.; Murali, Rajmohan; Wongvipat, John; Skaggs, Brian J.; Mündel, Peter; Weins, Astrid; Sawyers, Charles L.

doi:10.1073/pnas.1417297111

Cited by 38 publications

(48 citation statements)

References 40 publications

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“…More importantly, MAGI2 null mice show progressive proteinuria as early as 2 weeks postnatally [58]. In the present study, glomerular MAGI2 expression and its clinical implication were examined in many types of CKD using Nephroseq data, and the results showed significantly downregulated MAGI2 in CKDs, corroborating previous findings.…”

Section: Discussionsupporting

confidence: 88%

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

Zuo

Shen

Pan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Podocyte damage is associated with proteinuria, glomerulosclerosis and decline of renal function. This study aimed to screen critical genes associated with podocyte injury in chronic kidney disease (CKD) by weighted gene correlation network analysis (WGCNA), and explore related functions. Methods: GSE66107, GSE93798, GSE30528, GSE32591 gene expression data including podocyte injury models or glomeruli in CKD patients were downloaded from the GEO database. R was used for data analysis. Differentially expressed genes (DEGs) (FDR< 0.05 or |Fold Change|≥1.5) in GSE993395 were assessed by WGCNA. According to Gene Ontology (GO) and known podocyte standard genes (PSGs), podocyte injury-associated modules were defined, with hub genes selected based on average intramodular connectivity. The Cytoscape software was used for network visualization. Nephroseq was used to assess the clinical significance of hub genes. Small interfering RNA (siRNA) was used to evaluate the roles of hub genes in podocyte injury Results: Totally 7957 DEGs were screened, with 15 (co.DEGs) altered in all 4 datasets; 4031 DEGs were used for WGCNA, encompassing 12 modules. Green modules (most PSGs and co.DEGs) were significantly enriched in glomerular development, and considered podocyte injury-associated modules. Furthermore, MAGI2 (a hub gene) was also a co.DEG and PSG. Glomerular MAGI2 levels were reduced in various kidney diseases, and positively and negatively associated with glomerular filtration rate and urinary protein levels in CKD patients. Moreover, MAIG2 knockdown reduced NPHS2, CD2AP and SYNPO levels, and induced podocyte rearrangement and apoptosis. Conclusion: MAGI2 identified by WGCNA regulates cytoskeletal rearrangement in podocytes, with its loss predisposing to proteinuria and CKD.

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Section: Discussionsupporting

confidence: 88%

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

Zuo

Shen

Pan

et al. 2018

Cell Physiol Biochem

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“…33 Therefore, we tested whether PEC activation also occurs in Cd2ap À/À mice and whether it was delayed in Cd2ap À/À ;Ddn À/À mice. We analyzed the expression of the podocyte marker synaptopodin and the PEC marker PAX2 at 4, 5, and 6 weeks in kidneys of wild-type, Cd2ap À/À ;Ddn þ/þ , and Cd2ap À/À ; Ddn À/À mice ( Figure 5).…”

Section: Dendrin Ablation Improves Renal Survivalmentioning

confidence: 99%

Dendrin Ablation Prolongs Life Span by Delaying Kidney Failure

Weins

Wong

Basgen

et al. 2015

The American Journal of Pathology

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Podocyte loss is central to the progression of proteinuric kidney diseases leading to end-stage kidney disease (ESKD), requiring renal replacement therapy, such as dialysis. Despite modern tools and techniques, the 5-year mortality of some patients requiring dialysis remains at about 70% to 80%. Thus, there is a great unmet need for podocyte-specific treatments aimed at preventing podocyte loss and the ensuing development of ESKD. Here, we show that ablation of the podocyte death-promoting protein dendrin delays the onset of ESKD, thereby expanding the life span of mice lacking the adapter protein CD2AP. Ablation of dendrin delays onset and severity of proteinuria and podocyte loss. In addition, dendrin ablation ameliorates mesangial volume expansion and up-regulation of mesangial fibronectin expression, which is mediated by a podocyte-secreted factor. In conclusion, onset of ESKD and death can be markedly delayed by blocking the function of dendrin.

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“…2,3,7,8 Magi2-deleted mice display podocyte foot process effacement and severe proteinuria, with early death from end-stage renal failure. [9][10][11] We previously discovered recessive MAGI2 mutations as causing SRNS in humans and replicated that the regulation of RhoA activity omits pathogenesis. 2 To further characterize disease mechanisms of SRNS in MAGI2 loss of function, we generated stable CRISPR/Cas9-mediated zebrafish knockout (KO) lines.…”

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confidence: 67%

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

Jobst-Schwan

Hoogstraten

Kolvenbach

et al. 2019

Kidney International

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Recently, recessive mutations of MAGI2 were identified as a cause of steroid-resistant nephrotic syndrome (SRNS) in humans and mice. To further delineate the pathogenesis of MAGI2 loss of function, we generated stable knockout lines for the two zebrafish orthologues magi2a and magi2b by CRISPR/Cas9. We also developed a novel assay for the direct detection of proteinuria in zebrafish independent of transgenic background. Whereas knockout of magi2b did not yield a nephrotic syndrome phenotype, magi2a -/larvae developed ascites, periorbital edema, and proteinuria, as indicated by increased excretion of low molecular weight protein. Electron microscopy demonstrated extensive podocyte foot process effacement. As in human SRNS, we observed genotype/phenotype correlation, with edema onset occurring earlier in zebrafish with truncating alleles (5-6 days post fertilization) versus hypomorphic alleles (19-20 days post fertilization). Paradoxically, corticosteroid treatment exacerbated the phenotype, with earlier onset of edema. In contrast, treatment with cyclosporine A or tacrolimus had no significant effect. Although RhoA signaling has been implicated as a downstream mediator of MAGI2 activity, targeting of the RhoA pathway did not modify the nephrotic syndrome phenotype. In the first CRISPR/Cas9 zebrafish knockout model of SRNS, we found that corticosteroids may have a paradoxical effect in the setting of specific genetic mutations.

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MAGI-2 scaffold protein is critical for kidney barrier function

Cited by 38 publications

References 40 publications

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

Dendrin Ablation Prolongs Life Span by Delaying Kidney Failure

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

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