Interleukin-11 protects against renal ischemia and reperfusion injury

Lee, H. Thomas; Park, Sang Won; Kim, Mihwa; Ham, Ahrom; Anderson, Lana J.; Brown, Kevin M.; D’Agati, Vivette D.; Cox, George N.

doi:10.1152/ajprenal.00220.2012

Cited by 57 publications

(58 citation statements)

References 61 publications

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“…Thus, IL11 can be added to the growing list of HIF-regulated genes. Interestingly, it has been recently shown that IL-11 increases HIF-1a nuclear translocation and transcriptional activity in human renal proximal tube cells during ischemia reperfusion, suggesting the existence of a positive feedback loop between IL-11 and HIF-1 (46).…”

Section: Discussionmentioning

confidence: 99%

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

Onnis

Fer²,

Rapisarda³

et al. 2013

J. Clin. Invest.

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IL-11 and its receptor, IL-11Ra, are expressed in human cancers; however, the functional role of IL-11 in tumor progression is not known. We found that IL11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells and that expression of IL11 mRNA was dependent, at least in part, on HIF-1. A cooperative interaction between HIF-1 and AP-1 mediated transcriptional activation of the IL11 promoter. Additionally, we found that human cancer cells expressed a functional IL-11Ra subunit, which triggered signal transduction either by exogenous recombinant human IL-11 or by autocrine production of IL-11 in cells cultured under hypoxic conditions. Silencing of IL11 dramatically abrogated the ability of hypoxia to increase anchorage-independent growth and significantly reduced tumor growth in xenograft models. Notably, these results were phenocopied by partial knockdown of STAT1 in a human prostate cancer cell line (PC3), suggesting that this pathway may play an important role in mediating the effects of IL-11 under hypoxic conditions. In conclusion, these results identify IL11 as an oxygen-and VHL-regulated gene and provide evidence of a pathway "hijacked" by hypoxic cancer cells that may contribute to tumor progression.

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Section: Discussionmentioning

confidence: 99%

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

Onnis

Fer²,

Rapisarda³

et al. 2013

J. Clin. Invest.

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“…IL11 encodes IL-11, a hematopoietic cytokine with antiapoptotic and antinecrotic properties, ameliorates renal injury when administered exogenously. 37 Endogenous IL11 transcripts rose at early time points in two separate kidney fibrosis models, UUO and unilateral ischemia-reperfusion injury, and fell back toward normal expression levels later during the disease course ( Figure 6, A and B). NKD2 mRNA was strongly upregulated at later time points in fibrosis.…”

Section: Validation Of Novel Myofibroblast Gene Expressionmentioning

confidence: 96%

Translational Profiles of Medullary Myofibroblasts during Kidney Fibrosis

Grgic

Krautzberger

Hofmeister

et al. 2014

Journal of the American Society of Nephrology

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Myofibroblasts secrete matrix during chronic injury, and their ablation ameliorates fibrosis. Development of new biomarkers and therapies for CKD will be aided by a detailed analysis of myofibroblast gene expression during the early stages of fibrosis. However, dissociating myofibroblasts from fibrotic kidney is challenging. We therefore adapted translational ribosome affinity purification (TRAP) to isolate and profile mRNA from myofibroblasts and their precursors during kidney fibrosis. We generated and characterized a transgenic mouse expressing an enhanced green fluorescent protein (eGFP)-tagged L10a ribosomal subunit protein under control of the collagen1a1 promoter. We developed a one-step procedure for isolation of polysomal RNA from collagen1a1-eGFPL10a mice subject to unilateral ureteral obstruction and analyzed and validated the resulting transcriptional profiles. Pathway analysis revealed strong gene signatures for cell proliferation, migration, and shape change. Numerous novel genes and candidate biomarkers were upregulated during fibrosis, specifically in myofibroblasts, and we validated these results by quantitative PCR, in situ, and Western blot analysis. This study provides a comprehensive analysis of early myofibroblast gene expression during kidney fibrosis and introduces a new technique for cell-specific polysomal mRNA isolation in kidney injury models that is suited for RNA-sequencing technologies.

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“…80,81 Interestingly, HIF-1a signaling is critical for IL-11-mediated protection against ischemic AKI. 82 Moreover, ischemia or hypoxia promotes HIF-1a-dependent transcriptional regulation of adenosine-generating enzymes (CD39 or CD73) 80 that can directly stimulate IL-11 synthesis. 79 Previous studies also suggest that a widely used volatile anesthetic, isoflurane, increases HIF-1a expression in a renal carcinoma cell line and in the rabbit myocardium.…”

Section: Volatile Anesthetics and Renal Protection Mechanismsmentioning

confidence: 99%

Volatile Anesthetics and AKI

Fukazawa

Lee

2014

Journal of the American Society of Nephrology

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AKI is a major clinical problem with extremely high mortality and morbidity. Kidney hypoxia or ischemia-reperfusion injury inevitably occurs during surgery involving renal or aortic vascular occlusion and is one of the leading causes of perioperative AKI. Despite the growing incidence and tremendous clinical and financial burden of AKI, there is currently no effective therapy for this condition. The pathophysiology of AKI is orchestrated by renal tubular and endothelial cell necrosis and apoptosis, leukocyte infiltration, and the production and release of proinflammatory cytokines and reactive oxygen species. Effective management strategies require multimodal inhibition of these injury processes. Despite the past theoretical concerns about the nephrotoxic effects of several clinically utilized volatile anesthetics, recent studies suggest that modern halogenated volatile anesthetics induce potent anti-inflammatory, antinecrotic, and antiapoptotic effects that protect against ischemic AKI. Therefore, the renal protective properties of volatile anesthetics may provide clinically useful therapeutic intervention to treat and/or prevent perioperative AKI. In this review, we outline the history of volatile anesthetics and their effect on kidney function, briefly review the studies on volatile anesthetic-induced renal protection, and summarize the basic cellular mechanisms of volatile anesthetic-mediated protection against ischemic AKI.

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Interleukin-11 protects against renal ischemia and reperfusion injury

Cited by 57 publications

References 61 publications

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

Translational Profiles of Medullary Myofibroblasts during Kidney Fibrosis

Volatile Anesthetics and AKI

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