<scp>AXL</scp>
            targeting reduces fibrosis development in experimental unilateral ureteral obstruction

Landolt, Lea; Furriol, Jessica; Babickova, Janka; Ahmed, Lavina; Eikrem, Øystein; Skogstrand, Trude; Scherer, Andreas; Suliman, Salwa; Leh, Sabine; Lorens, James B.; Gausdal, Gro; Marti, Hanspeter; Osman, Tarig Al-Hadi

doi:10.14814/phy2.14091

Cited by 16 publications

(14 citation statements)

References 74 publications

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“…Furthermore, Ruxolitinib treatment blocked TGF-β1 -induced E-cadherin downregulation in NRK-52E cells. Transcription factors snail and twist have been shown involved in renal tubular epithelial cell EMT [22,23]. Our study demonstrated that Ruxolitinib treatment suppressed snail and twist upregulation in both UUO kidneys and TGF-β1 -treated NRK-52E cells.…”

Section: Discussionsupporting

confidence: 50%

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

et al. 2020

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Ruxolitinib is a selective inhibitor of Jak1/2. Downstream signaling pathways of Jak, such as Stat3 and Akt/mTOR, are overactivated and contribute to renal interstitial fibrosis. Therefore, we explored the effect of Ruxolitinib on this pathological process. Unilateral ureteral obstruction (UUO) models and TGF-β1-treated fibroblasts and renal tubular epithelial cells were adopted in this study. Ruxolitinib was administered to UUO mice and TGF-β1-treated cells. Kidneys from UUO mice with Ruxolitinib treatment displayed less tubular injuries compared with those without Ruxolitinib treatment. Ruxolitinib treatment suppressed fibroblast activation and extracellular matrix (ECM) production in UUO kidneys and TGF-β1-treated fibroblasts. Ruxolitinib treatment also blocked epithelial-mesenchymal transition (EMT) in UUO kidneys and TGF-β 1-treated renal tubular epithelial cells. Moreover, Ruxolitinib treatment alleviated UUO-induced inflammation, oxidative stress and apoptosis. Mechanistically, Ruxolitinib treatment attenuated activation of both Stat3 and Akt/mTOR/Yap pathways. In conclusion, Ruxolitinib treatment can ameliorate UUO-induced renal interstitial fibrosis, suggesting that Ruxolitinib may be potentially used to treat fibrotic kidney disease.

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Section: Discussionsupporting

confidence: 50%

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

et al. 2020

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“…Bemcentinib (BGB324/R-428), a first-in-class highly selective oral AXL tyrosine kinase inhibitor in phase II development, was also predicted to stably occupy the nsp16/nsp10 activating interface. Although mainly recognized for its ability to block epithelial-mesenchymal transition phenomena in various cancer types [93][94][95], bemcentinib is now known for its anti-inflammatory and anti-fibrotic roles in non-cancer diseases [96,97], which are two phenotypic aspects that might be relevant in the therapeutic management of COVID-19. Moreover, AXL is a family member of the TAM receptor tyrosine kinases that operates both as a pleiotropic inhibitor of the innate immune response and a docking site during the cellular entry of some viruses [98][99][100].…”

Section: Bemcentinibmentioning

confidence: 99%

Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA

Encinar

Menendez

2020

Viruses

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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2′-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation.

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“…Animal handling and sample collection were previously described in full detail. 16 Briefly, eight-to nine-week-old male C57Bl/6JOlaHSD mice were acquired from Envigo (Horst, the Netherlands) and kept and managed in the local animal facility at the Department of Biomedicine, University of Bergen, Norway. All surgeries were performed under general anaesthesia with isoflurane gas.…”

Section: Animals and Sample Collectionmentioning

confidence: 99%

“…All analyses were performed using the R programming language. Sequencing data were published in a previous study from our group 16 and are available in the repository Gene Expression Omnibus https://www. ncbi.nlm.nih.gov/geo/query/ acc.cgi?acc=GSE12 3674.…”

Section: Total Gene Expression Analysismentioning

confidence: 99%

“…14,15 A previous study from our group demonstrated the effectiveness of the Axl inhibitor bemcentinib in alleviating fibrosis development in a murine unilateral ureteral obstruction (UUO) model. 16 This model is widely used to elucidate the pathogenesis of obstructive nephropathy and the mechanisms responsible for progressive renal fibrosis, and as a model to investigate fibrosis attenuating treatments. 17 Furthermore, since it reflects the progression of acute kidney injury (AKI) to CDK, UUO provides an important model to study mitochondrial dysfunction in kidney diseases.…”

mentioning

confidence: 99%

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Axl‐inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model

Hoel

Osman

Hoel

et al. 2021

J Cellular Molecular Medi

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Renal fibrosis is a progressive histological manifestation leading to chronic kidney disease (CKD) and associated with mitochondrial dysfunction. In previous work, we showed that Bemcentinib, an Axl receptor tyrosine kinase inhibitor, reduced fibrosis development. In this study, to investigate its effects on mitochondrial dysfunction in renal fibrosis, we analysed genome‐wide transcriptomics data from a unilateral ureter obstruction (UUO) murine model in the presence or absence of bemcentinib (n = 6 per group) and SHAM‐operated (n = 4) mice. Kidney ligation resulted in dysregulation of mitochondria‐related pathways, with a significant reduction in the expression of oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), citric acid cycle (TCA), response to reactive oxygen species and amino acid metabolism‐related genes. Bemcentinib treatment increased the expression of these genes. In contrast, AKT/PI3K signalling pathway genes were up‐regulated upon UUO, but bemcentinib largely inhibited their expression. At the functional level, ligation reduced mitochondrial biomass, which was increased upon bemcentinib treatment. Serum metabolomics analysis also showed a normalizing amino acid profile in UUO, compared with SHAM‐operated mice following bemcentinib treatment. Our data suggest that mitochondria and mitochondria‐related pathways are dramatically affected by UUO surgery and treatment with Axl‐inhibitor bemcentinib partially reverses these effects.

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AXL targeting reduces fibrosis development in experimental unilateral ureteral obstruction

Cited by 16 publications

References 74 publications

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA

Axl‐inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model

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