CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin-induced Nephropathy and Kidney Inflammation

Donner, Aaron J; Yeh, Shu-Hui; Hung, Gene; Graham, Mark; Crooke, Rosanne M.; Mullick, Adam E.

doi:10.1038/mtna.2015.40

Cited by 25 publications

(20 citation statements)

References 44 publications

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“…Preclinical and clinical studies have shown that the pro-inflammatory cytokine CD40 plays a crucial role in the onset and maintenance of the inflammatory reaction [14], and activation of CD40 contributes to renal inflammation and injury in vivo and in vitro [40, 41]. In the present study, TNF-α significantly increased CD40 expression at mRNA and protein levels in IMCD cells in a time- and concentration-dependent manner.…”

Section: Discussionsupporting

confidence: 60%

MiR-21 Regulates TNF-α-Induced CD40 Expression via the SIRT1-NF-κB Pathway in Renal Inner Medullary Collecting Duct Cells

Lin

Geng

Zhao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Recent studies have indicated that microRNA-21 (miR-21) is involved in the inflammatory response in relation to renal disease. Sirtuin1 (SIRT1) exerts renoprotective properties by counteracting inflammation. The activation of CD40 triggers inflammation that participates in renal inflammation and injury. The relationship between miR-21, SIRT1 and CD40, however, remains elusive. Methods: Immunohistochemistry, small-interfering RNA (siRNA) transfection, quantitative real-time PCR and western blotting were applied to assess the morphological, functional and molecular mechanisms in primary cultured renal inner medullary collecting duct (IMCD) cells. Results: TNF-α induced miR-21, CD40 and acetylated-NF-κBp65 (Ac-p65) expressions and reduced SIRT1 expression in IMCD cells. miR-21 mimics increased SIRT1 expression and attenuated Ac-p65 and CD40 expressions in TNF-α-induced IMCD cells, and the corresponding changes were observed with a miR-21 inhibitor. SIRT1 overexpression or activation by SRT1720 diminished TNF-α-induced CD40 and Ac-p65 expressions, which was reversed by SIRT1 siRNA or the inhibitors Ex527 and sirtinol and augmented by pretreatment with NF-κB siRNA. Further study found that the inhibitory effect of miR-21 on Ac-p65 and CD40 expressions was impeded by pretreatment with SIRT1 siRNA. Conclusion: The present study indicates that miR-21 inhibits TNF-α-induced CD40 expression in IMCD cells via the SIRT1-NF-κB signalling pathway, which provides new insight in understanding the anti-inflammatory effect of miR-21.

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Section: Discussionsupporting

confidence: 60%

MiR-21 Regulates TNF-α-Induced CD40 Expression via the SIRT1-NF-κB Pathway in Renal Inner Medullary Collecting Duct Cells

Lin

Geng

Zhao

et al. 2017

Cell Physiol Biochem

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“…The following groups were formed: control (no antisense oligonucleotide [ASO] treatment), ASO not specific to any murine transcript (ASO scramble ) and ASO SAA (specific for the murine Saa1 and Saa2 transcripts). Both ASOs are based on generation 2.5 chemistry, which consisted of 2-O, 4-C-[(S)-ethylidene]-D-ribose ('cEt') modified sugars for the three terminal 5′ and 3′ nucleotides that flank a central ten-nucleotide DNA gap [28]. The ASO treatment was performed via i.p.…”

Section: Methodsmentioning

confidence: 99%

Serum amyloid A links endotoxaemia to weight gain and insulin resistance in mice

et al. 2016

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Aims/hypothesis Pre-adipocytes and adipocytes are responsive to the acute phase protein serum amyloid A (SAA). The combined effects triggered by SAA encompass an increase in preadipocyte proliferation, an induction of TNF-α and IL-6 release and a decrease in glucose uptake in mature adipocytes, strongly supporting a role for SAA in obesity and related comorbidities. This study addressed whether SAA depletion modulates weight gain and insulin resistance induced by a high-fat diet (HFD). Methods Male Swiss Webster mice were fed an HFD for 10 weeks under an SAA-targeted antisense oligonucleotide (ASO SAA ) treatment in order to evaluate the role of SAA in weight gain. Results With ASO SAA treatment, mice receiving an HFD did not differ in energy intake when compared with their controls, but were prevented from gaining weight and developing insulin resistance. The phenotype was characterised by a lack of adipose tissue expansion, with low accumulation of epididymal, retroperitoneal and subcutaneous fat content and decreased inflammatory markers, such as SAA3 and toll-like receptor (TLR)-4 expression, as well as macrophage infiltration into the adipose tissue. Furthermore, a metabolic status similar to chow-fed mice counterparts could be observed, with equivalent levels of leptin, adiponectin, IGF-I, SAA, fasting glucose and insulin, and remarkable improvement in glucose and insulin tolerance test profiles. Surprisingly, the expected HFD-induced metabolic endotoxaemia was also prevented by the ASO SAA treatment. Conclusions/interpretationThis study provides further evidence of the role of SAA in weight gain and insulin resistance. Moreover, we also suggest that beyond its proliferative and inflammatory effects, SAA is part of the lipopolysaccharide signalling pathway that links inflammation to obesity and insulin resistance.

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“…While monoclonal antibody strategies encountered thrombotic complications, a late-generation antisense oligonucleotide approach has promise as an approach to limiting the action of this signaling dyad (102). A small molecule inhibitor of CD40 interaction with its signal transducing partner TRAF also holds interest in this regard (103).…”

Section: Beyond Cantos: Other Targets Other Indicationsmentioning

confidence: 99%

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

Libby

2017

Journal of the American College of Cardiology

508

350

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Inflammatory pathways drive atherogenesis and link traditional risk factors to atherosclerosis and its complications. One inflammatory mediator has come to the fore as a therapeutic target in cardiovascular disease. The experimental and clinical evidence reviewed here support interleukin-1 beta (IL-1β) as both a local vascular and systemic contributor in this regard. Intrinsic vascular wall cells and lesional leukocytes alike can produce this cytokine. Local stimuli in the plaque favor the generation of active IL-1β through the action of a molecular assembly known as the inflammasome. Clinically applicable interventions that interfere with IL-1 action can improve cardiovascular outcomes, ushering in a new era of anti-inflammatory therapies for atherosclerosis. The translational path described here illustrates how advances in basic vascular biology may transform therapy. Biomarker-directed application of anti-inflammatory interventions promises to help us achieve a more precise and personalized allocation of therapy for our cardiovascular patients.

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CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin-induced Nephropathy and Kidney Inflammation

Cited by 25 publications

References 44 publications

MiR-21 Regulates TNF-α-Induced CD40 Expression via the SIRT1-NF-κB Pathway in Renal Inner Medullary Collecting Duct Cells

MiR-21 Regulates TNF-α-Induced CD40 Expression via the SIRT1-NF-κB Pathway in Renal Inner Medullary Collecting Duct Cells

Serum amyloid A links endotoxaemia to weight gain and insulin resistance in mice

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

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