Ischemia-reperfusion induces G-CSF gene expression by renal medullary thick ascending limb cells in vivo and in vitro

Zhang, Ying; Woodward, Vanessa K.; Shelton, John M.; Richardson, James A.; Zhou, Xin J.; Link, Daniel C.; Kielar, Mariusz L.; Jeyarajah, D. Rohan; Lu, Christopher Y.

doi:10.1152/ajprenal.00379.2002

Cited by 41 publications

(35 citation statements)

References 55 publications

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“…7 It is known that inflammation is a crucial role in the development of AKI; 6,7,26 systemic inflammation could be secondary to local kidney inflammation 11,12 and systemic inflammation accompanied during AKI. 7,[13][14][15][16][17] Human studies showed that AKI is associated with organ failures and cytokine activation. 27 In addition, the relationship between inflammation and AKI severity is most powerful.…”

Section: Discussionmentioning

confidence: 99%

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Can neutrophil–lymphocyte ratio be independent risk factor for predicting acute kidney injury in patients with severe sepsis?

Yılmaz

Çakmak

İnan³

et al. 2014

Renal Failure

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Aim: Neutrophil-lymphocyte ratio (NLR) is an easily calculated, sensitive, and accurate marker for prognosis and diagnosing sepsis, cardiovascular disease and cancer. As sepsis and septic shock are main causes of acute kidney injury (AKI) intensive care unit (ICU), we investigated whether NLR is an early predictor of AKI in patients with severe sepsis. We compared NLR's predictive power with that of other inflammation-related variables. Methods: Between December 2011 and November 2013, we enrolled 118 consecutive cases with severe sepsis admitted to ICU in this retrospective study. Levels of C-reactive protein (CRP), NLR, and white blood cell count (WBC) were recorded on admission and patients' renal function was monitored for seven consecutive days. Results: The rate of AKI occurrence 7 days after enrollment was 57.6%. NLR levels were higher in the AKI group (Group 1) than in the non-AKI group (Group 2) on the day of ICU admission (p50.001). AKI development was independently associated with NLR, Acute Physiology and Chronic Health Evaluation II (APACHE II) and duration of invasive mechanical ventilation (MV) in multivariate logistic regression analysis. The area under the receiver-operating characteristic (ROC) curve of NLR for predicting AKI was 0.986, which was superior to WBC and CRP (p50.05). The cut-off value of 10.15 for NLR had the highest validity for predicting AKI in patients with severe sepsis. The sensitivity, specificity, negative-predictive value (NPV), and positive-predictive value (PPV), for this cut-off value was 90.2%, 92.9%, 90.4%, and 92.7%, respectively. Conclusion: NLR is superior to CRP, and WBC for predicting the development of AKI in patients with severe sepsis.

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Section: Discussionmentioning

confidence: 99%

“…11,12 There is typically a systemic inflammation during AKI. 5,7,[13][14][15][16][17] Neutrophil-lymphocyte ratio (NLR) is an indicator of systemic inflammation, calculated easily from complete blood count. 18 Some studies showed that NLR is promising marker in predicting bacteremia in patients with emergency medical admissions.…”

Section: Introductionmentioning

confidence: 99%

Can neutrophil–lymphocyte ratio be independent risk factor for predicting acute kidney injury in patients with severe sepsis?

Yılmaz

Çakmak

İnan³

et al. 2014

Renal Failure

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“…This was subcloned into pDrive cloning Vector (Qiagen PCR Cloning Kit) and S35 labeled sense and antisense probes were prepared. Previously published techniques from our laboratory were used for the in situ hybridiation (44,61). In sections adjacent to those probed for CXCL2 in situ, collecting duct were identified by antibody to aquaphorin 3, and proximal tubules were identified by staining with TRITC-coupled LTA (43).…”

Section: Animals B6ifnarmentioning

confidence: 99%

Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI

Winterberg

Wang

Lin

et al. 2013

American Journal of Physiology-Renal Physiology

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ously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of ␣-subtypes of type I interferons (IFN␣s). We found that genetic knockout of the common type I IFN receptor (IFNARI Ϫ/Ϫ ) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFN␤ and IFN␣s: IFN␤ expression peaks at 4 h, earlier than IFN␣s, and continues at the same level at 24 h; expression of IFN␣s also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFN␣s relative to baseline is much greater than that of IFN␤. We show by immunohistology and study of isolated cells that IFN␤ is produced by renal leukocytes and IFN␣s are produced by renal tubules. IRF1, IFN␣s, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFN␣ expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFN␣s. Furthermore, we found that IFN␣ stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells:AKI; innate immunity; type I interferon ISCHEMIC ACUTE KIDNEY INJURY (AKI) causes significant shortterm morbidity and mortality (33) and, over the long-term, may contribute to the increasing incidence of end-stage renal disease (15,41,55). Despite these major clinical implications, there is currently no specific therapy beyond supportive care (33). A major insight into pathogenesis was the recognition that the initial ischemic insult elicits maladaptive responses that exacerbate the injury (31). In other words, the ultimate amount of renal injury is determined not only by the direct effects of hypoxia but also by the ensuing maladaptive responses. Understanding the latter may reveal novel therapeutic targets for the treatment of AKI.One maladaptive response is the production of type I interferons (IFNs). Knockout of the gene for the ␣-chain (IFNAR1) of the type I interferon (IFN) receptor heterodimer ameliorated ischemic AKI and decreased renal inflammation in mice (11). Such receptor knockout prevents signaling by, and thus the biological effects of, all type I IFNs (32, 37). These include IFN-, IFN-, IFNε, about which little is known, and also the better understood IFN␤ and the IFN␣ family (which has 13 members in humans, 14 in mice).1 Their biological effects include increasing inflammation and increasing apoptosis (11). These effects should increase injury during ischemic AKI and are in addition to the more widely known antiviral effects of type I IFNs (36, 54).Despite their im...

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“…The IL-6 fragment for the in situ probe was amplified from an ischemic kidney cDNA library (11). The details of probe preparation and in situ hybridization were published previously by our group (12). To stain with F4/80 antibody, the kidney sections were deparaffinized, blocked with Protein Block Serum (cat.…”

Section: In Situ Hybridization For Il-6 Mrna and Immunohistology For mentioning

confidence: 99%

Maladaptive Role of IL-6 in Ischemic Acute Renal Failure

Kielar¹,

John²,

Bennett³

et al. 2005

Journal of the American Society of Nephrology

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181

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The role of IL-6 was investigated in murine ischemic acute renal failure. The renal pedicles were clamped for 17 min, and the mice were studied at various times after reperfusion. We found that serum IL-6 increased after murine ischemic renal injury. This increase was associated with increased IL-6 mRNA in the ischemic kidney but not in the contralateral kidney or the liver. Maximal IL-6 production occurred at 4 to 8 h and decreased to baseline by 24 h. Reperfusion of the kidney was required for IL-6 production. In situ hybridization and immunohistochemistry showed that macrophages infiltrated areas adjacent to the vascular bundles in the outer medulla within hours of reperfusion and showed that these macrophages produced IL-6 mRNA. For understanding how macrophages were stimulated to produce IL-6, an in vitro model in which S3 proximal tubular cells were injured by reactive oxygen species was set up. These injured cells released molecules that activated macrophages to produce IL-6 in vitro. IL-6 that was produced in response to renal ischemia was maladaptive because transgenic knockout of IL-6 ameliorated renal injury as measured by serum creatinine and histology. IL-6 transgenic knockout mice were lethally irradiated, and their bone marrow was reconstituted with wild-type IL-6 cells. Such bone marrow transfers abolished the protective effects of transgenic IL-6 knockout. It is concluded that macrophages infiltrate the area of the vascular bundles of the outer medulla, these macrophages produce IL-6, and this IL-6 exacerbates ischemic murine acute renal failure.

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Ischemia-reperfusion induces G-CSF gene expression by renal medullary thick ascending limb cells in vivo and in vitro

Cited by 41 publications

References 55 publications

Can neutrophil–lymphocyte ratio be independent risk factor for predicting acute kidney injury in patients with severe sepsis?

Can neutrophil–lymphocyte ratio be independent risk factor for predicting acute kidney injury in patients with severe sepsis?

Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI

Maladaptive Role of IL-6 in Ischemic Acute Renal Failure

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