Erythropoietin expands a stromal cell population that can mediate renoprotection

Bi, Baoyuan; Guo, J.G.; Marlier, Arnaud; Lin, Shin Ru; Cantley, Lloyd G.

doi:10.1152/ajprenal.90218.2008

Cited by 43 publications

(35 citation statements)

References 38 publications

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“…In the present study, we demonstrated that 6 months of 8-OHdG = 8-hydroxydeoxyguanosin, BNP = brain natriuretic peptide, ADMA =asymmetric dimethylarginine, baPWV = brachial ankle pulse wave velocity, IMT = intima-media thickness, SBP = systolic blood pressure, DBP = diastolic blood pressure, PGN = proliferative glomerulonephritis, FGS = focal glomerulosclerosis, ARB = angiotensin II receptor blocker, ACEI = angiotensin converting enzyme inhibitor, CTR=cardio-thracic ratio, IVCD=inferior vena cava dimention therapy with recombinant human EPO significantly reduced urinary protein excretion and the urinary L-FABP level in pre-dialysis CKD patients with anemia, thereby suggesting that EPO exerts renoprotective effects. The levels of urinary 8-OHdG, plasma BNP and serum ADMA were also reduced after 6 months of EPO treatment, suggesting that EPO also exerts an anti-oxidative and cardioprotective effect and improves NO bioavailability.…”

Section: Discussionsupporting

confidence: 66%

“…EPO ameliorates tubulointerstitial injury in the model of unilateral ureteral obstruction by inhibiting inflammation, interstitial fibrosis and tubular apoptosis (26). Bone marrow stromal cells (BMSC) exert a renoprotective effect in tubular injury via the secretion of factors that reduce apoptosis and increase proliferation of tubular epithelial cells (8). EPO receptors are expressed on the surface of BMSCs and EPO protects BMSCs from cell death induced by serum deprivation and stimulates BMSC proliferation in vitro (8).…”

Section: Discussionmentioning

confidence: 99%

“…Kasap et al (7) reported that EPO had no significant protective effect upon renal function or chronic fibrosis in animal models but it did reduce tubular changes, apoptosis and oxidative stress. In addition, Bi et al (8) reported that EPO can protect tubular cells from various injurious stimuli both in vitro and in vivo. However, there is little known regarding the effect of EPO on urinary L-FABP and urinary 8-OHdG levels in CKD patients.…”

Section: Introductionmentioning

confidence: 99%

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Renovascular Protective Effects of Erythropoietin in Patients with Chronic Kidney Disease

et al. 2011

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Background/Aims Erythropoietin (EPO) has been widely used for the treatment of anemia in chronic kidney disease (CKD). A growing body of evidence indicates that the therapeutic benefits of EPO could extend beyond the improvement of anemia. The aim of the present study was to determine whether EPO affects renovascular and oxidative stress biomarkers in pre-dialysis CKD patients with anemia. Methods The study was a single-arm prospective study. Fifteen CKD patients (9 males and 6 females, mean age 63 years) with anemia (mean Hb: 8.1 g/dL) were treated with recombinant human EPO; 12,000 U administered subcutaneously once every 2 weeks. Various parameters were measured before and 6 months after treatment. These included serum hemoglobin (Hb), creatinine, estimated glomerular filtration rate (eGFR), proteinuria, urinary liver-type fatty acid binding protein (L-FABP -a biomarker of renal injury), urinary 8-hydroxydeoxyguanosine (8-OHdG -a marker of oxidative stress), serum asymmetrical dimethylarginine (ADMA), carotid artery intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) as vascular markers and plasma brain natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF) as cardiac function markers and cardio-thoracic ratio (CTR) and inferior vena cava dimension (IVCS) as extra fluid retention markers. Results After 6 months, serum Hb was significantly increased (p<0.001) and urinary levels of protein, L-FABP and 8-OHdG, carotid IMT, baPWV, plasma BNP and serum ADMA levels were significantly decreased (p<0.001). Serum creatinine, eGFR, LVEF, CTR and IVCS showed little difference throughout the experimental period. Conclusion These data suggest that recombinant human EPO may ameliorate renal injury, oxidative stress and progression of atherosclerosis in addition to improving anemia in CKD patients.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Renovascular Protective Effects of Erythropoietin in Patients with Chronic Kidney Disease

et al. 2011

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“…It is plausible that certain Hif-regulated molecules enhance tissue repair during recovery from AKI. For example, Epo, which is induced in our model, has been shown to accelerate repair in experimental models of both, AKI and CKD (5). Another example is stromal cell-derived factor-1, a HIF-1-induced chemokine, that enhances recruitment of progenitor cells to regenerating tissues (7).…”

Section: Discussionmentioning

confidence: 86%

Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury

Kapitsinou

Jaffe

Michael

et al. 2012

American Journal of Physiology-Renal Physiology

112

105

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-Acute kidney injury (AKI) due to ischemia is an important contributor to the progression of chronic kidney disease (CKD). Key mediators of cellular adaptation to hypoxia are oxygen-sensitive hypoxia-inducible factors (HIF), which are regulated by prolyl-4-hydroxylase domain (PHD)-containing dioxygenases. While activation of HIF protects from ischemic cell death, HIF has been shown to promote fibrosis in experimental models of CKD. The impact of HIF activation on AKI-induced fibrosis has not been defined. Here, we investigated the role of pharmacologic HIF activation in AKI-associated fibrosis and inflammation. We found that pharmacologic inhibition of HIF prolyl hydroxylation before AKI ameliorated fibrosis and prevented anemia, while inhibition of HIF prolyl hydroxylation in the early recovery phase of AKI did not affect short-or long-term clinical outcome. Therefore, preischemic targeting of the PHD/HIF pathway represents an effective therapeutic strategy for the prevention of CKD resulting from AKI, and it warrants further investigation in clinical trials.hypoxia-inducible factor; HIF prolyl-4-hydroxylases ISCHEMIA-REPERFUSION INJURY (IRI) in the kidney is a major cause of acute kidney injury (AKI). Despite advances in understanding the pathophysiology of AKI and important improvements in clinical care, the overall prognosis of patients with AKI remains poor and is associated with a mortality rate of 40 -80% in the intensive care setting (31). Similarly, preventive strategies have been unsuccessful as the incidence of AKI is increasing and will nearly double over the next decade as the population ages (1). In addition to challenges of acute clinical management, AKI is increasingly recognized as an important contributor to end-stage renal disease (ESRD) (1,8,16,20); ϳ6% of patients with AKI progress to ESRD within 2 yr of diagnosis (29). Similarly, animal studies examining long-term outcomes of AKI have detected irreversible functional and structural changes, including tubulointerstitial fibrosis and capillary rarefaction. These facts highlight the urgent need for novel therapeutic approaches that aim at preventing and/or reversing the pathophysiologic sequelae of AKI.Hypoxic preconditioning, by which short exposure to hypoxia induces resistance to subsequent ischemic injury, has received much attention as a potential novel therapeutic strategy in the prevention of AKI (12). Key mediators of cellular adaptation to oxygen deprivation are hypoxia-inducible factor (HIF)-1 and -2, heterodimeric basic helix-loop-helix transcription factors, which regulate cellular energy metabolism, angiogenesis, erythropoiesis, apoptosis, and cell proliferation. The activity of HIF is controlled by oxygen-, iron-, and ascorbatedependent dioxygenases, also known as prolyl-4-hydroxylase domain-containing proteins 1-3 (PHD1-3), which use 2-oxoglutarate as substrate for the hydroxylation of specific proline residues in HIF-␣. This permits binding to the pVHL-E3 ubiquitin ligase complex, which results in proteasomal degradation of HIF...

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“…The degree of AKI, extent of fibrosis and organization in repair, dedifferentiation of tubules, and continuing hypoxia through vascular rarefaction all contribute to the insidious progression to CKD (5,31,44,64). EPO has the ability to stimulate growth and differentiation of various lineages of cells, including those of mesenchymal, possibly profibrotic, origin (7,13,15,39,46). To date there have been few reports of the effects of delivery of rhEPO for renoprotection in AKI on any subsequent CKD induction.…”

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confidence: 99%

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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Erythropoietin expands a stromal cell population that can mediate renoprotection

Cited by 43 publications

References 38 publications

Renovascular Protective Effects of Erythropoietin in Patients with Chronic Kidney Disease

Renovascular Protective Effects of Erythropoietin in Patients with Chronic Kidney Disease

Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury

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

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