Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta

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

doi:10.1016/j.ejphar.2011.01.043

Cited by 15 publications

(15 citation statements)

References 47 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).…”

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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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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“…Besides, in our study Nx rats were charactered with endothelial dysfunction, evidenced by a relaxant response to ACh, which corresponding to the previous experimental investigations [24][25][26][27]. Clinical study also showed that atherosclerosis can be accelerated in patient with impaired endothelium-dependent vasodilatation [28].…”

Section: Discussionsupporting

confidence: 48%

“…Clinical study also showed that atherosclerosis can be accelerated in patient with impaired endothelium-dependent vasodilatation [28]. Given these results, renal mass reduction features progressive injury to the renal microvascular endothelium, resulting to glomerular sclerosis and other injuries [25]. In our study, although HQD had no effect on the increased systolic blood pressure in Nx rats, the treatment can still significantly reverse the functional and structural alterations found in rats with 5/6 Nx, which suggest the beneficial effect of this compound in renoprotection.…”

Section: Discussionmentioning

confidence: 97%

Improvement of Huangqi Decoction on Endothelial Dysfunction in 5/6 Nephrectomized Rats

Chu

Wang

Mao

et al. 2016

Cell Physiol Biochem

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Background/Aims: Endothelial dysfunction is a major factor in the progression of chronic kidney disease, which correlates with oxidative stress and NO deficiency. Huangqi decoction (HQD) is a potential anti-oxidant ingredient in renoprotection. However, the underlying mechanisms remained identified. Therefore, we investigated whether HQD exhibit improvement in endothelial dysfunction in the 5/6 nephrectomy (Nx) rat model. Methods: Male Wistar rats (180 - 250 g) were divided into sham, Nx and Nx + HQD (0.05, 0.15 and 0.45 g/kg) group, respectively. Renal function and histology were examined with ELISA and Immunohistochemical analysis. Endothelium-dependent relaxation of rat aortas was investigated by isometric tension recordings. Oxidative stress and NO bioavailability were detected by ELISA, DHE-staining, DAF-2 staining and western blotting. Results: Compared with Nx rats, HQD treatment reversed the functional and structural changes of kidney significantly. Besides, endothelium-dependent relaxation of rat aortas was also improved by HQD treatment. NADPH oxidase and ROS generation were inhibited while NO bioavailability was enhanced. Conclusion: HQD can act as a potent prescription for the treatment of endothelium related vascular complications.

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“…The PI3K/Akt pathway is known to lead to increased eNOS expression and activity in vascular endothelial cells (Alessi and Cohen, 1998;Downward, 1998). It has been recently reported that EPO increases aortic eNOS expression and plasma NOx levels, via phosphorylation of Akt, in accordance with improvement in endothelial function in Nx and diabetic rats (Toba et al, 2011;Wang et al, 2013). Furthermore, it has also been shown that the preventative effect of EPO against vascular remodeling and endothelial dysfunction is lacking in eNOS-deficient mice after wire injury (d'Uscio et al, 2007).…”

Section: Discussionmentioning

confidence: 97%

“…Erythropoietin (EPO) receptors are widely distributed in both hematopoietic cells and non-hematopoietic cells, including neurons, cardiomyocytes, peritubular and mesangial cells, and vascular cells such as endothelial and smooth muscle cells (Khoshdel et al, 2008). Although several reports have demonstrated that ESAs have potential benefits against endothelial dysfunction (Bahlmann et al, 2004;Mohler et al, 2011;Toba et al, 2011), these endothelial protective effects of ESAs have been observed under doses that had no influence on hemoglobin, and it is unclear whether appropriate treatment of ESA exerts endothelial protective effects under amelioration of anemia.…”

Section: Introductionmentioning

confidence: 98%

Epoetin beta pegol prevents endothelial dysfunction as evaluated by flow-mediated dilation in chronic kidney disease rats

Serizawa¹,

Tashiro²,

Aizawa³

et al. 2015

European Journal of Pharmacology

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Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta

Cited by 15 publications

References 47 publications

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

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

Improvement of Huangqi Decoction on Endothelial Dysfunction in 5/6 Nephrectomized Rats

Epoetin beta pegol prevents endothelial dysfunction as evaluated by flow-mediated dilation in chronic kidney disease rats

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