Interleukin-6 Stimulates Tubular Regeneration in Rats with Glycerol-Induced Acute Renal Failure

Homsi, Eduardo; Ribeiro-Alves, Maria Almerinda; Faria, José B. Lopes de; Dias, E.P.O.

doi:10.1159/000064478

Cited by 33 publications

(22 citation statements)

References 33 publications

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“…Whereas in other examples of organ failure IL-6 induces resistance to injury, 20,34 -36 this study and previous reports 37 showed that IL-6 treatment does not prevent AKI. As shown here, the lack of IL-6R expression in the kidney precludes an IL-6 -mediated protective response through the classical signaling pathway.…”

Section: Discussionmentioning

confidence: 44%

IL-6/IL-6R Axis Plays a Critical Role in Acute Kidney Injury

Nechemia-Arbely¹,

Barkan²,

Pizov³

et al. 2008

Journal of the American Society of Nephrology

327

279

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The response to tissue injury involves the coordination of inflammatory and repair processes. IL-6 expression correlates with the onset and severity of acute kidney injury (AKI), but its contribution to pathogenesis remains unclear. This study established a critical role for IL-6 in both the inflammatory response and the resolution of AKI. IL-6 -deficient mice were resistant to HgCl 2 -induced AKI compared with wild-type mice. The accumulation of peritubular neutrophils was lower in IL-6 -deficient mice than in wild-type mice, and neutrophil depletion before HgCl 2 administration in wild-type mice significantly reduced AKI; these results demonstrate the critical role of IL-6 signaling in the injurious inflammatory process in AKI. Renal IL-6 expression and STAT3 activation in renal tubular epithelial cells significantly increased during the development of injury, suggesting active IL-6 signaling. Although a lack of renal IL-6 receptors (IL-6R) precludes the activation of classical signaling pathways, IL-6 can stimulate target cells together with a soluble form of the IL-6R (sIL-6R) in a process termed trans-signaling. During injury, serum sIL-6R levels increased three-fold, suggesting a possible role for IL-6 trans-signaling in AKI. Stimulation of IL-6 trans-signaling with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI. IL-6/sIL-6R reduced lipid peroxidation after injury, suggesting that its protective effect may be largely mediated through amelioration of oxidative stress. In summary, IL-6 simultaneously promotes an injurious inflammatory response and, through a mechanism of transsignaling, protects the kidney from further injury.

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Section: Discussionmentioning

confidence: 44%

IL-6/IL-6R Axis Plays a Critical Role in Acute Kidney Injury

Nechemia-Arbely¹,

Barkan²,

Pizov³

et al. 2008

Journal of the American Society of Nephrology

327

279

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“…However, two members of the IL-6 family, IL-6 and CNTF, have been shown to participate in renal tubule cell regeneration after kidney injury. Administration of IL-6 stimulates tubule regeneration after glycerol-induced acute renal failure (40), and CNTF has been shown to be involved in renal tubule regeneration after ischemia-reperfusion injury (33). These observations suggest the importance of the role of the IL-6 family in renal tubule cell regeneration.…”

Section: Discussionmentioning

confidence: 99%

Leukemia Inhibitory Factor Is Involved in Tubular Regeneration after Experimental Acute Renal Failure

Yoshino

Monkawa

Tsuji

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Leukemia inhibitory factor (LIF) is known to play a crucial role in the conversion of mesenchyme into epithelium during nephrogenesis. This study was carried out to test the hypothesis that LIF and LIF receptor (LIFR) are involved in the renal epithelial regeneration after acute renal failure. First, the authors investigated the spatiotemporal expression of LIF and LIFR in fetal and adult rat kidney. In developing kidney, LIF was expressed in the ureteric buds and LIFR was located in nephrogenic mesenchyme and the ureteric buds; in adult kidney, LIF and LIFR expression was confined to the collecting ducts. Next, the authors examined the expression of LIF and LIFR during the recovery phase after ischemia-reperfusion injury. Real-time PCR analysis revealed that LIF mRNA expression was significantly increased from day 1 to day 7 after reperfusion and that LIFR mRNA was upregulated from day 4 to day 14. Histologic analysis demonstrated that the increased expression of LIF mRNA and protein was most marked in the outer medulla, especially in the S3 segment of the proximal tubules. To elucidate the mitogenic role of LIF in the regeneration process, cultured rat renal epithelial (NRK 52E) cells were subjected to ATP depletion (an in vitro model of acute renal failure), and LIF expression was found to be enhanced during recovery after ATP depletion. Blockade of endogenous LIF with a neutralizing antibody significantly reduced the cell number and DNA synthesis during the recovery period. These results suggest that LIF participates in the regeneration process after tubular injury.

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“…Interestingly, IL-6, one of the cytokines mediated by IL-1F6, is associated with renal pathogenesis such as tubular regeneration and is excreted in the urine in the case of renal disease. 39,40 In future studies, urinary IL-1F6 protein and/or mRNA as biomarker of renal injury should be evaluated about the detection sensitivity and disease specificity.…”

Section: Pathological Significance Of Il-1f6 In Renal Diseasementioning

confidence: 99%

Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions

Ichii

Otsuka

Sasaki

et al. 2010

Laboratory Investigation

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Identification of factors that exacerbate a disease is important for the development of biomarkers. In this study, we discovered ectopic overexpression of interleukin-1 family, member-6 (IL-1F6) in several murine renal diseases. IL-1F6 participates in cytokine/chemokine production in the epithelium. In PCR array analysis for inflammatory mediators, Il1f6 showed the highest expression in the kidney of the B6.MRLc1 glomerulonephritis model. IL-1F6 was localized in the epithelium from the DCTs to CCDs, which showed tubular dilations or epithelial deciduations. Ultrastructual examination of the epithelial cells revealed that IL-1F6 was localized on the cytoplasmic ribosome, vesicles, and nucleus. In and around these tubules, we found infiltrations of CD3-positive T-cells and nestin-or a-smooth-muscle actin-positive mesenchymal cells. Expression of the IL-1F6 protein and Il1f6 mRNA in the kidney was increased by the development of TILs in the B6.MRLc1 model and in lupus (BXSB, NZB/WF1, and MRL/lpr), nephrotic syndrome (ICGN), and streptozotocin-induced diabetic models. IL-1F6 was also detected in the epithelia having squamous or deciduous contours in other organs such as the skin, esophagus, thymus, or uterus. In vitro analysis using M-1 cells from the murine collecting duct revealed that Il1f6 mRNA induction was related to the upregulation of IL-6, TGF-b receptor-1, and mesenchymal markers and to the downregulation of epithelial markers and changes in the squamous cells of the epithelium. Interestingly, urine Il1f6 mRNA expression was detected earlier than renal dysfunctions in these mouse models. Ectopic overexpression of IL-1F6 in kidneys is associated with TILs and especially with cell infiltrations and changes in epithelial morphology. We propose that local overexpression of IL-1F6 is related to the development of TILs.

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Interleukin-6 Stimulates Tubular Regeneration in Rats with Glycerol-Induced Acute Renal Failure

Cited by 33 publications

References 33 publications

IL-6/IL-6R Axis Plays a Critical Role in Acute Kidney Injury

IL-6/IL-6R Axis Plays a Critical Role in Acute Kidney Injury

Leukemia Inhibitory Factor Is Involved in Tubular Regeneration after Experimental Acute Renal Failure

Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions

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