Erythropoietin prevents vascular inflammation and oxidative stress in subtotal nephrectomized rat aorta beyond haematopoiesis

Toba, Hiroe; Nakashima, K; Oshima, Yutaka; Kojima, Yushi; Tojo, Chisato; Nakano, Arisa; Wang, Jiahong; Kobara, Miyuki; Nakata, Tetsuo

doi:10.1111/j.1440-1681.2010.05445.x

Cited by 23 publications

(16 citation statements)

References 58 publications

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“…For example, in CKD due to unilateral ureteral obstruction (UUO) in rats, rhEPO delivered daily after induction of UUO reduced the profibrotic growth factor trans-forming growth factor-␤ (TGF-␤) and decreased fibrosis and epithelial-to-mesenchymal transition (EMT) (45,60). Similar results have been published in the 5 ⁄6 nephrectomy CKD model (4,61,62) and in nephrotoxic animal models of CKD (33,43). In the brain, EPO protected neurons after hypoxic injury but also stimulated growth of glial cells (69) and fibroblasts (53).…”

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confidence: 70%

Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury

Gobé

Bennett

West

et al. 2014

American Journal of Physiology-Renal Physiology

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Treatment of renal ischemia-reperfusion (IR) injury with recombinant human erythropoietin (rhEPO) reduces acute kidney injury and improves function. We aimed to investigate whether progression to chronic kidney disease associated with acute injury was also reduced by rhEPO treatment, using in vivo and in vitro models. Rats were subjected to bilateral 40-min renal ischemia, and kidneys were studied at 4, 7, and 28 days postreperfusion for renal function, tubular injury and repair, inflammation, and fibrosis. Acute injury was modulated using rhEPO (1,000 or 5,000 IU/kg, intraperitoneally) at the time of reperfusion. Renal tubular epithelial cells or fibroblasts in culture were subjected to hypoxia or oxidative stress, with or without rhEPO (200 IU/ml), and fibrogenesis was studied. The results of the in vivo model confirmed functional and structural improvement with rhEPO at 4 days post-IR ( P < 0.05). At 7 days post-IR, fibrosis and myofibroblast stimulation were increased with IR with and without rhEPO ( P < 0.01). However, at 28 days post-IR, renal fibrosis and myofibroblast numbers were significantly greater with IR plus rhEPO ( P < 0.01) compared with IR only. Mechanistically, rhEPO stimulated profibrotic transforming growth factor-β, oxidative stress (marker 8-hydroxy-deoxyguanosine), and phosphorylation of the signal transduction protein extracellular signal-regulated kinase. In vitro, rhEPO protected tubular epithelium from apoptosis but stimulated epithelial-to-mesenchymal transition and also protected and activated fibroblasts, particularly with oxidative stress. In summary, although rhEPO was protective of renal function and structure in acute kidney injury, the supraphysiological dose needed for renoprotection contributed to fibrogenesis and stimulated chronic kidney disease in the long term.

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supporting

confidence: 70%

Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury

Gobé

Bennett

West

et al. 2014

American Journal of Physiology-Renal Physiology

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“…Marked suppression of hepcidin was observed as early as 24 h after EPO administration; hepcidin suppression persisted throughout the week, with incomplete recovery occurring over a 2-week period, suggesting that the effect of EPO was direct and independent of an increase in hematocrit. Another study, by Toba et al [38], also showed that low-dose ESA normalized endothelial function, vascular inflammation and oxidative stress in rats with renal ablation beyond hematopoiesis. One can assume, as suggested by the results of this study, that decreased inflammation and oxidative stress may be an important determinant in the reduction of hepcidin levels by EPO treatment.…”

Section: Causal Role Of Hepcidin In Anemia Of Inflammation and Effectmentioning

confidence: 99%

Renal Anemia of Inflammation: The Name Is Self-Explanatory

et al. 2011

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Background: Anemia is inevitable as chronic kidney disease (CKD) advances. With the advent of erythropoietin-stimulating agents (ESAs), considerable improvement has been achieved in the management of anemia. However, some patients show a reduced response to ESAs. Methods: Many factors affect the response to ESA treatment. CKD is now considered as an inflammatory disorder and this understanding led to the recognition of the central role of inflammation in ESA resistance. Inflammation is related to untoward outcomes, including atherosclerosis and anemia, in the CKD population. Furthermore, recognition of deleterious effects of proinflammatory markers at different levels of erythropoiesis led to a change in the name of ‘anemia of chronic disease’ to anemia of inflammation. Results: The discovery of hepcidin as the major controller of iron metabolism in anemia of inflammation answered many questions regarding the interaction of erythropoietin, iron and bone marrow. Hepcidin production in the liver is driven by three major factors: inflammation, iron overload and anemia/hypoxia. Hepcidin levels are increased in patients with CKD due to the interaction of many factors; a comprehensive understanding of these pathways is thus critical in the effort to alleviate anemia of inflammation and ESA resistance. Conclusion: In this review, we discussed the epidemiology, determinants and consequences of anemia of inflammation in CKD patients with special emphasis on the central role of hepcidin along with molecular pathways driving its production.

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“…Some studies evaluated the effects of ROS on vascular properties in rat aorta (Toba et al, 2010;Olukman et al, 2010). Others tried to reveal the mechanisms involved in ROS-induced cardiovascular disease inside the brainstem (Zanzinger et al, 2009;Valenti et al, 2011a;Campos et al, 2011).…”

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confidence: 99%