NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus

Brightbill, Hans; Suto, Eric; Blaquière, Nicole; Ramamoorthi, Nandhini; Sujatha-Bhaskar, Swathi; Gogol, Emily; Castanedo, Georgette; Jackson, Benjamin T.; Kwon, Youngsu; Haller, Susan; Lesch, Justin; Bents, Karin; Everett, Christine; Kohli, Pawan Bir; Linge, Sandra; Christian, Laura S.; Barrett, Kathy; Jaochico, Allan; Berezhkovskiy, Leonid M.; Fan, Peter W.; Modrušan, Zora; Veliz, Kelli; Townsend, Michael J.; DeVoss, Jason; Johnson, Adam R.; Godemann, Robert; Lee, Wyne P.; Austin, Cary D.; McKenzie, Brent; Hackney, Jason A.; Crawford, James J.; Staben, Steven T.; Ismaili, Moulay Hicham Alaoui; Wu, Lawren C.; Ghilardi, Nico

doi:10.1038/s41467-017-02672-0

Cited by 101 publications

(91 citation statements)

References 72 publications

(86 reference statements)

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“…We hypothesized that these caspase-8-independent phenotypes were due to aberrant activation of the non-canonical NF-kB pathway, as indicated by the processing of NF-kB2 p100 into p52 ( Figure 4A). R26-CreER T2 cIap1 À/À cIap2 fl/fl Ripk3 À/À Casp8 À/À mice dosed with a NIK inhibitor (Brightbill et al, 2018) before and during tamoxifen treatment contained more p100 and less p52 in the large intestine, consistent with a degree of pathway inhibition ( Figure 4B). Neutrophils in the spleen (Figures 4C, 4D, and S4D) and IL-12p40 and IL-10 in the serum ( Figure 4E) were now reduced.…”

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confidence: 61%

Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation

Zhang¹,

Webster²,

Dugger³

et al. 2019

Cell Reports

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confidence: 61%

Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation

Zhang¹,

Webster²,

Dugger³

et al. 2019

Cell Reports

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“…Interestingly, our analysis predicted increased nuclear factor-kB pathway activity in LN and it has been shown that selective inhibition of nuclear factor-kB inducing kinase reduces disease severity in an LN mouse model. 46 Furthermore, we predicted increased phosphoinositide 3-kinase activity in FSGS and a human causing FSGS mutation in the anilin gene was shown to increase phosphoinositide 3-kinase activity in podocytes. 47 We also used a signature-matching algorithm to explore potential drugs that could revert the disease phenotype.…”

Section: Resultsmentioning

confidence: 93%

A Functional Landscape of CKD Entities From Public Transcriptomic Data

Tajti

Kuppe

Antoranz

et al. 2020

Kidney International Reports

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Introduction: To develop effective therapies and identify novel early biomarkers for chronic kidney disease, an understanding of the molecular mechanisms orchestrating it is essential. We here set out to understand how differences in chronic kidney disease (CKD) origin are reflected in gene expression. To this end, we integrated publicly available human glomerular microarray gene expression data for 9 kidney disease entities that account for most of CKD worldwide. Our primary goal was to demonstrate the possibilities and potential on data analysis and integration to the nephrology community. Methods: We integrated data from 5 publicly available studies and compared glomerular gene expression profiles of disease with that of controls from nontumor parts of kidney cancer nephrectomy tissues. A major challenge was the integration of the data from different sources, platforms, and conditions that we mitigated with a bespoke stringent procedure. Results: We performed a global transcriptome-based delineation of different kidney disease entities, obtaining a transcriptomic diffusion map of their similarities and differences based on the genes that acquire a consistent differential expression between each kidney disease entity and nephrectomy tissue. We derived functional insights by inferring the activity of signaling pathways and transcription factors from the collected gene expression data and identified potential drug candidates based on expression signature matching. We validated representative findings by immunostaining in human kidney biopsies indicating, for example, that the transcription factor FOXM1 is significantly and specifically expressed in parietal epithelial cells in rapidly progressive glomerulonephritis (RPGN) whereas not expressed in control kidney tissue. Furthermore, we found drug candidates by matching the signature on expression of drugs to that of the CKD entities, in particular, the Food and Drug Administration-approved drug nilotinib. Conclusion: These results provide a foundation to comprehend the specific molecular mechanisms underlying different kidney disease entities that can pave the way to identify biomarkers and potential therapeutic targets. To facilitate further use, we provide our results as a free interactive Web application: https://saezlab.shinyapps.io/ckd_landscape/. However, because of the limitations of the data and the difficulties in its integration, any specific result should be considered with caution. Indeed, we consider this study rather an illustration of the value of functional genomics and integration of existing data.

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“…MiRNAs (as: miR-155, miR-663a/miR-423-5p, and Let-7) are well represented in both nuclear factor (NF)-κB and IFN-γ causing LN (Honarpisheh, Köhler, von Rauchhaupt, & Lech, 2018). NF-κB can induce inflammation and fibrosis in LN by regulating the transcription of proinflammatory cytokines (Brightbill et al, 2018). Klotho regulates NF-κB activation and participates in protecting the kidneys by mitigating oxidative stress (Zou, Wu, He, Ma, & Gao, 2018).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Micro-RNA199 in systemic lupus erythematosus patients with and without lupus nephritis

Elessawi

Radwan

El-Barbary

2020

Journal of Radiation Research and Applied Sciences

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Skin and kidney are commonly affected in systemic lupus erythematosus (SLE) with similar molecular mechanisms. Although clinical indicators of renal injury in SLE are fairly uncontroversial, few biomarkers are reliable. The role of Micro-RNAs (miRNAs) in lupus nephritis (LN) pathogenesis has been investigated. The aim of work is to evaluate miRNA199 expression in SLE Egyptian patients and their association with LN. This is a case-control study involving 98 SLE patients with and without LN (LN and non-LN groups), and 20 age-and sex-matched healthy controls were carried out to detect miRNA199 with quantitative Real-Time Polymerase chain reaction methods. The SLE disease activity index (SLEDAI) was assessed. The mean disease duration was 5.9 ± 3.4 and 6.4 ± 4.4 months in LN and non-LN, and SLEDAI was 11.98 ± 5.3 and 10.5 ± 3.8 in LN and non-LN. miRNA199 expression was significantly decreased in patient groups compared to controls (1.01 ± 0.03) (P = 0.0001) and in LN (0.41 ± 0.21) compared to non-LN group (0.55 ± 0.15) (P = 0.002). There was no correlation between miRNA199 expression and SLEDAI or other clinical and laboratory data of the patients. In conclusion, miRNA199 may play a role in SLE activity and helping in the early diagnosis of LN.

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NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus

Cited by 101 publications

References 72 publications

Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation

Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation

A Functional Landscape of CKD Entities From Public Transcriptomic Data

Evaluation of Micro-RNA199 in systemic lupus erythematosus patients with and without lupus nephritis

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