IκB Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD

Chen, Jianmin; Kieswich, Julius; Chiazza, Fausto; Moyes, Amie J; Gobbetti, Thomas; Purvis, Gareth S. D.; Salvatori, Daniela; Patel, Nimesh S. A.; Perretti, Mauro; Hobbs, Adrian J.; Collino, Massimo; Yaqoob, Muhammad; Thiemermann, Christoph

doi:10.1681/asn.2015060670

Cited by 47 publications

(50 citation statements)

References 58 publications

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“…ELISA for ANXA1 Concentrations of ANXA1 in human plasma, mouse serum or protein lysates from heart and kidney were measured by ELISA as previously reported [21][22][23] /Tyr 204 on extracellular signal-regulated kinase (ERK1/2)/p-ERK1/2 (New England Biolabs) was measured by semi-quantitative western blot analyses in mouse heart and kidney tissue as described previously [20,25] (see ESM Methods for further details).…”

Section: Methodsmentioning

confidence: 99%

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

et al. 2017

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Aims/hypothesis Microvascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes. Methods ANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1 −/− mice. Diabetic mice were treated with human recombinant (hr)ANXA1(1 μg, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.).Results Plasma levels of ANXA1 were elevated in individuals with type 1 diabetes with/without nephropathy compared with healthy individuals (66.0 ± 4.2/64.0 ± 4 ng/ml vs 35.9 ± 2.3 ng/ml; p < 0.05). Compared with diabetic wild-type (WT) mice, diabetic Anxa1 −/− mice exhibited a worse diabetic phenotype and developed more severe cardiac (ejection fraction; 76.1 ± 1.6% vs 49.9 ± 0.9%) and renal dysfunction (proteinuria; 89.3 ± 5.0 μg/ mg vs 113.3 ± 5.5 μg/mg). Mechanistically, compared with nondiabetic WT mice, the degree of the phosphorylation of mitogenactivated protein kinases (MAPKs) p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was significantly higher in non-diabetic Anxa1 −/− mice in both the heart and kidney, and was further enhanced after STZ-induced type 1 diabetes. Prophylactic treatment with hrANXA1 (weeks 1-13) attenuated both cardiac (ejection fraction; 54.0 ± 1.6% vs 72.4 ± 1.0%) and renal (proteinuria; 89.3 ± 5.0 μg/mg vs 53.1 ± 3.4 μg/mg) dysfunction associated with STZ-induced diabetes, while therapeutic administration of hrANXA1 (weeks 8-13), after significant cardiac and renal dysfunction had already developed, halted the further functional decline in cardiac and renal function seen in diabetic mice administered vehicle. In addition, administration of hrANXA1 attenuated the increase in phosphorylation of p38, JNK and ERK, and restored phosphorylation of Akt in diabetic mice. Conclusions/interpretationOverall, these results demonstrate that ANXA1 plasma levels are elevated in individuals with Christoph Thiemermann and Egle Solito contributed equally to this work.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4469-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Methodsmentioning

confidence: 99%

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

et al. 2017

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“…Additionally, because both NOD1/2 and TLRs signal through IKK/NF‐κB, IKK is an obvious target. Different IKK inhibitors either improve survival of animals with polymicrobial sepsis or at least ameliorate deterioration of vital functions seen in these animals …”

Section: Potential Clinical Relevance Of Nod‐tlr Synergymentioning

confidence: 99%

Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

Pashenkov

Murugina

Будихина

et al. 2018

Journal of Leukocyte Biology

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Interactions between pattern recognition receptors (PRRs) shape innate immune responses to particular classes of pathogens. Here, we review interactions between TLRs and nucleotide‐binding oligomerization domain 1 and 2 (NOD1 and NOD2) receptors, two major groups of PRRs involved in innate recognition of bacteria. Most of experimental data both in vitro and in vivo suggest that NODs and TLRs synergize with each other at inducing the production of cytokines and antimicrobial peptides. Molecular mechanisms of this synergy remain poorly understood, although several scenarios can be proposed: (i) direct interactions of signaling pathways downstream of NODs and TLRs; (ii) mutual transcriptional regulation of unique components of NOD‐dependent and TLR‐dependent signaling pathways; and (iii) interactions at the post‐transcriptional level. Potential practical implications of NOD‐TLR synergy are dual. In sepsis, where synergistic effects probably contribute to excessive proinflammatory cytokine production, blockade of NOD1, and/or NOD2 in addition to TLR4 blockade may be required to achieve therapeutic benefit. On the other hand, synergistic combinations of relatively small doses of NOD and TLR agonists administered before infection could be used to boost innate resistance against bacterial pathogens.

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“…In this regard, studies have documented oxidative stress and inflammation in the cardiac tissue of animals with experimental CKD. [17][18][19] CKD also results in mitochondrial depletion and dysfunction in the myocardium and skeletal muscle. 20,21 In fact, mitochondria from cardiac tissue of CKD animals were unable to retain calcium, had diminished cytochrome C levels and decreased respiratory function.…”

Section: Discussionmentioning

confidence: 99%

LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease

Suematsu

Jing

Nunes

et al. 2018

Journal of Cardiac Failure

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Highlights The effect of LCZ696 (Sacubitril/valsartan) against cardiorenal syndrome is proposed. LCZ696 more improved CKD related heart failure than valsartan therapy alone. LCZ696 attenuated CKD related cardiac hypertrophy and fibrosis and aortic fibrosis. Effects of LCZ696 for heart are mediated by anti-inflammation and oxidative stress. LCZ696 also improved indicators of mitochondrial mass/function. AbstractBackground: Chronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis and

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IκB Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD

Cited by 47 publications

References 58 publications

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease

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