Interleukin-6 plays a protective role in development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors

Mitazaki, Satoru; Honma, Shigeyoshi; Suto, Miwako; Kato, Natsuki; Hiraiwa, Kouichi; Yoshida, Makoto; Abe, Sumiko

doi:10.1016/j.lfs.2011.04.016

Cited by 35 publications

(20 citation statements)

References 39 publications

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“…In a previous study, increased MPO activity and inflammation (infiltration of leukocytes and proinflammatory cytokines) caused oxidative stress and tissue damage in cisplatin-induced acute renal injury. 47 In our experiment, reduced kidney MPO activity after MSC injection indicated a possible decrease in neutrophil accumulation or activity. This finding indicates that MSCs could be a therapeutic approach as a potent immunosuppressive for the attenuation of histopathologic signs of UUO.…”

Section: Discussionsupporting

confidence: 52%

Untitled

Özbek

Adaş²,

Ötünçtemur³

et al. 2015

Exp Clin Transplant

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Objectives: Mesenchymal stem cells hold promise for renal disease treatment. Vascular endothelial growth factor may heal tubule-interstitial fibrosis in unilateral ureteral obstruction by inhibiting epithelial-mesenchymal transition. We investigated the protective effect of vascular endothelial growth factor in transfected mesenchymal stem cells in unilateral ureteral obstruction-induced renal injury in rats. Materials and Methods: Male Wistar Albino rats (32 rats; weight, 250-300 g) were divided into 4 equal groups: group 1, control; group 2, unilateral ureteral obstruction; group 3, unilateral ureteral obstruction and mesenchymal stem cells; and group 4, unilateral ureteral obstruction and vascular endothelial growth factor-transfected mesenchymal stem cells. Vascular endothelial growth factor-transfected mesenchymal stem cells were administered intravenously before onset of unilateral ureteral obstruction. On day 14, the rats were killed and kidneys were retrieved. Tubular necrosis, mono-nuclear cell infiltration, and interstitial fibrosis were evaluated in paraffin blocks. We evaluated green fluorescent proteinpositive and vascular endothelial growth factorpositive cells; anti-inflammatory (Prostaglandin E2 Receptor) and interleukin 1 receptor antagonist), proinflammatory/anti-inflammatory (interleukin 6), and proinflammatory (MPO) cytokine expression levels; and levels of nitric oxide; transforming growth factor β1, E-cadherin, and hydroxyproline. Results: Green fluorescent protein-positive cells were negative in the renal parenchyma in groups 1 and 2 and positive in groups 3 and 4. Vascular endothelial growth factor levels were significantly higher in group 4. Transforming growth factor β1, nitric oxide, and E-cadherin levels were significantly higher in the unilateral ureteral obstruction than control group; however, in the study groups, these values were not significantly different from the unilateral ureteral obstruction group. In stem celltransplanted tissue samples, EP3, interleukin 1 receptor antagonist, and interleukin 6 levels were elevated, but MPO expression levels were low. Although there were significant differences for tubular necrosis and fibrosis in group 2, there were significant reductions in tubular injury and fibrosis in groups 3 and 4. Conclusions: Systemic stem cells transplanted into the kidney protected against unilateral ureteral obstruction-induced renal epithelial-mesenchymal transition and renal fibrosis.

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Section: Discussionsupporting

confidence: 52%

Untitled

Özbek

Adaş²,

Ötünçtemur³

et al. 2015

Exp Clin Transplant

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“…In one study, they showed that IL-6 levels were increased in proximal tubular cells after cisplatin treatment and that IL-6 knockout (IL-6 −/− ) mice presented more severe AKI with Bax followed by an increase in Bcl-2 and Bcl-xL [15] . This same group demonstrated that IL-6 −/− mice showed more oxidative stress with increased cox-2 expression and ERK phosphorylation, while superoxide dismutase activity was decreased [14] . More recently, the use of dimethylthiourea (DMTU), a hydroxyl radical scavenger, was shown to protect mice from cisplatin-induced AKI by increasing IL-6, Bcl-xL and Nrf2 [13] .…”

Section: Discussionmentioning

confidence: 81%

Long-Term Aerobic Exercise Protects against Cisplatin-Induced Nephrotoxicity by Modulating the Expression of IL-6 and HO-1

et al. 2014

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Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI). In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg) in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX). The group submitted to exercise before cisplatin administration (CIS-EX) exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS). Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney.

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“…IL-6 KO mice are resistant to HgCl 2 -induced AKI, yet IL-6 trans-signaling prevents AKI perhaps due to upregulation of anti-oxidant pathways [50]. IL-6 deficiency also accelerates cisplatin-induced AKI [56], and investigators have proposed that IL-6 may be protective in ischemic renal failure and in a mouse model of rhabdomyolysis-induced AKI [57,58]. These variable outcomes in IL-6 KO mice could be due to the doses of injurious factors, experimental time course and definitions of AKI.…”

Section: Discussionmentioning

confidence: 99%

Podocytes Express IL-6 and Lipocalin 2/ Neutrophil Gelatinase-Associated Lipocalin in Lipopolysaccharide-Induced Acute Glomerular Injury

Lee

Borsting

Declèves

et al. 2012

Nephron Exp Nephrol

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Background/Aims: Acute kidney injury (AKI) contributes to significant morbidity and mortality in the intensive care unit (ICU). Plasma levels of interleukin (IL)-6 predict the development of AKI and are associated with higher mortality in ICU patients with AKI. Most studies in AKI have focused on the tubulo-interstitium, despite evidence of glomerular involvement. In the following study, our goals were to investigate the expression of IL-6 and its downstream mediators in septic-induced AKI. Methods: Podocytes were treated in vitro with lipopolysaccharide (LPS) and mice were treated with LPS, and we evaluated IL-6 expression by real-time PCR, ELISA and in situ RNA hybridization. Results: Following LPS stimulation, IL-6 is rapidly and highly induced in cultured podocytes and in vivo in glomeruli and infiltrating leukocytes. Surprisingly, in direct response to exogenous IL-6, podocytes produce lipocalin-2/neutrophil gelatinase-associated lipocalin (Lcn2/Ngal). LPS also potently induces Lcn2/Ngal expression in podocytes in culture and in glomeruli in vivo. Intense Lcn2/Ngal expression is also observed in IL-6 knockout mice, suggesting that while IL-6 may be sufficient to induce glomerular Lcn2/Ngal expression, it is not essential. Conclusions: The glomerulus is involved in septic AKI, and we demonstrate that podocytes secrete key mediators of AKI including IL-6 and Lcn2/Ngal.

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Interleukin-6 plays a protective role in development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors

Cited by 35 publications

References 39 publications

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Long-Term Aerobic Exercise Protects against Cisplatin-Induced Nephrotoxicity by Modulating the Expression of IL-6 and HO-1

Podocytes Express IL-6 and Lipocalin 2/ Neutrophil Gelatinase-Associated Lipocalin in Lipopolysaccharide-Induced Acute Glomerular Injury

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