255
Views
5
CrossRef citations to date
0
Altmetric
Review Article

Erythropoietin mediates brain-vascular-kidney crosstalk and may be a treatment target for pulmonary and resistant essential hypertension

, , , , &
Pages 197-209 | Received 18 Aug 2016, Accepted 29 Sep 2016, Published online: 27 Apr 2017

References

  • White LE, Chaudhary R, Moore LJ, et al. Hassoun, Surgical sepsis and organ crosstalk: the role of the kidney. J Surg Res 2011;167:306–315.
  • Mitaka C, Si MK, Tulafu M, et al. Effects of atrial natriuretic peptide on inter-organ crosstalk among the kidney, lung, and heart in a rat model of renal ischemia-reperfusion injury. Intensive Care Med Exp 2014;2:28.
  • Zhang LN, Li JX, Hao L, et al. Crosstalk between dopamine receptors and the Na(+)/K(+)-ATPase (review). Mol Med Rep 2013;8:1291–1299.
  • Tsai WC, Chen PS, Cross talk between renal and cardiac autonomic nerves: is this how renal denervation works? J Cardiovasc Electrophysiol 2014;25:1257–1258.
  • Lincevicius GS, Shimoura CG, Nishi EE, et al. Aldosterone contributes to sympathoexcitation in renovascular hypertension. Am J Hypertension 2015;28:1083–1090.
  • Souma T, Suzuki N, Yamamoto M. Renal erythropoietin-producing cells in health and disease. Frontiers Physiol 2015;6:167.
  • Eckardt KU, Kurtz A, Bauer C. Triggering of erythropoietin production by hypoxia is inhibited by respiratory and metabolic acidosis. Am J Physiol 1990;258:R678–R683.
  • Quintas-Cardama A, Kantarjian H, et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discovery 2011;10:127–140.
  • Beleslin-Cokic BB, Cokic VP, Yu X, et al. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood 2004;104:2073–2080.
  • Teng R, Calvert JW, Sibmooh N, et al. Acute erythropoietin cardioprotection is mediated by endothelial response. Basic Res Cardiol 2011;106:343–354.
  • Zou YR, Zhang J, Wang J, et al. Erythropoietin receptor activation protects the kidney from ischemia/reperfusion-induced apoptosis by activating ERK/p53 signal pathway. Transplant Proc 2016;48:217–221.
  • Sakanaka M, Wen TC, Matsuda S, et al., In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 1998;95:4635–4640.
  • Roger SD, Baker LR, Raine AE. Autonomic dysfunction and the development of hypertension in patients treated with recombinant human erythropoietin (r-HuEPO). Clin Nephrol 1993;39:103–110.
  • Rosario R, Epstein M. Relationship between erythropoietin administration and alterations of renin-angiotensin-aldosterone. JRAAS 2006;7:135–138.
  • Kirsch KA, Schlemmer M, De Santo NG, et al. Erythropoietin as a volume-regulating hormone: an integrated view. Semin Nephrol 2005;25:388–391.
  • Montero D, Rauber S, Goetze JP, Lundby C. Reduction in central venous pressure enhances erythropoietin synthesis: role of volume-regulating hormones. Acta Physiol (Oxf, Engl) 2016.
  • Shafi NI, Andresen J, Marrelli SP, Bryan RM, Jr. Erythropoietin potentiates EDHF-mediated dilations in rat middle cerebral arteries. J Neurotrauma 2008;25:257–265.
  • Yada T, Shimokawa H, Hiramatsu O, et al. Erythropoietin enhances hydrogen peroxide-mediated dilatation of canine coronary collateral arterioles during myocardial ischemia in dogs in vivo. Am J Physiol Heart Circulatory Physiol 2010;299:H1928–1935.
  • Jain V, Lim M, Longo M, Fisk NM. Inhibitory effect of erythropoietin on contractility of human chorionic plate vessels. Am J Obstetrics Gynecol 2006;194:246.
  • Muller R, Steffen HM, Brunner R, et al. Changes in the alpha adrenergic system and increase in blood pressure with recombinant human erythropoietin (rHuEpo) therapy for renal anemia, Clinical and investigative medicine. Med Clin Exp 1991;14:614–622.
  • Suga M, Kurihara S, Iino Y, Terashi A. Acute effects of human recombinant erythropoietin on cardiovascular dynamics and vasoactive substances. Nihon Jinzo Gakkai shi 1996;38:634–639.
  • van Loon RL, Bartelds B, Wagener FA, et al. Erythropoietin attenuates pulmonary vascular remodeling in experimental pulmonary arterial hypertension through interplay between endothelial progenitor cells and heme oxygenase. Frontiers Pediatrics 2015;3:71.
  • Wincewicz A, Koda M, Sulkowska M, et al. STAT3 and hypoxia induced proteins–HIF-1alpha, EPO and EPOR in relation with Bax and Bcl-xL in nodal metastases of ductal breast cancers. Folia Histochem Cytobiol/Polish Acad Sci Polish Histochem Cytochem Soc 2009;47:425–430.
  • Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 2006;99:675–691.
  • Morakkabati N, Gollnick F, Meyer R, et al. Erythropoietin induces Ca2+ mobilization and contraction in rat mesangial and aortic smooth muscle cultures. Exp Hematol 1996;24:392–397.
  • Marrero MB, Venema RC, Ma H, et al. Erythropoietin receptor-operated Ca2+ channels: activation by phospholipase C-gamma 1. Kidney Int 1998;53:1259–1268.
  • Bode-Boger SM, Boger RH, Kuhn M, et al. Recombinant human erythropoietin enhances vasoconstrictor tone via endothelin-1 and constrictor prostanoids. Kidney Int 1996;50:1255–1261.
  • Rodrigue ME, Lacasse MS, Lariviere R, Lebel M. Cyclooxygenase inhibition with acetylsalicylic acid unmasks a role for prostacyclin in erythropoietin-induced hypertension in uremic rats. Can J Physiol Pharmacol 2005;83:467–475.
  • Wada Y, Matsuoka H, Tamai O, et al. Erythropoietin impairs endothelium-dependent vasorelaxation through cyclooxygenase-dependent mechanisms in humans. Am J Hypertens 1999;12:980–987.
  • Lebel M, Lacasse MS, Lariviere R, et al. Plasma and blood vessel endothelin-1 concentrations in hypertensive uremic rats treated with erythropoietin. Clin Exp Hypertens (New York, NY: 1993) 1998;20:939–951.
  • Vogel V, Kramer HJ, Backer A, et al. Effects of erythropoietin on endothelin-1 synthesis and the cellular calcium messenger system in vascular endothelial cells. Am J Hypertens 1997;10:289–296.
  • Kang DH, Yoon KI, Han DS. Acute effects of recombinant human erythropoietin on plasma levels of proendothelin-1 and endothelin-1 in haemodialysis patients. Nephrol Dialysis Transplant Off Publ Eur Dialysis Transplant Assoc Eur Renal Assoc 1998;13:2877–2883.
  • Briet M, Barhoumi T, Mian MO, et al. Effects of recombinant human erythropoietin on resistance artery endothelial function in stage 4 chronic kidney disease. J Am Heart Assoc 2013;2:e000128.
  • Wang XQ, Vaziri ND. Erythropoietin depresses nitric oxide synthase expression by human endothelial cells. Hypertension 1999;33:894–899.
  • Banerjee D, Rodriguez M, Nag M, Adamson JW. Exposure of endothelial cells to recombinant human erythropoietin induces nitric oxide synthase activity. Kidney Int 2000;57:1895–1904.
  • Kusano E, Akimoto T, Inoue M, et al. Human recombinant erythropoietin inhibits interleukin-1beta-stimulated nitric oxide and cyclic guanosine monophosphate production in cultured rat vascular smooth-muscle cells. Nephrol Dialysis Transplant Off Publ Eur Dialysis Transplant Assoc Eur Renal Assoc 1999;14:597–603.
  • Beleslin-Cokic BB, Cokic VP, Wang L, et al. Erythropoietin and hypoxia increase erythropoietin receptor and nitric oxide levels in lung microvascular endothelial cells. Cytokine 2011;54:129–135.
  • Fu W, Liao X, Ruan J, et al. Recombinant human erythropoietin preconditioning attenuates liver ischemia reperfusion injury through the phosphatidylinositol-3 kinase/AKT/endothelial nitric oxide synthase pathway. J Surg Res 2013;183:876–884.
  • Souza AC, Volpini RA, Shimizu MH, et al. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-kappaB and upregulating endothelial nitric oxide synthase. AmJ Physiol Renal Physiol 2012;302:F1045–F1054.
  • Ozden H, Durmaz R, Kanbak G, et al. Erythropoietin prevents nitric oxide and cathepsin-mediated neuronal death in focal brain ischemia. Brain Res 2011;1370:185–193.
  • Vaziri ND, Zhou XJ, Naqvi F, et al. Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure. Am J Physiol 1996;271:E113–E122.
  • Shimada N, Saka S, Sekizuka K, et al. Increased endothelin: nitric oxide ratio is associated with erythropoietin-induced hypertension in hemodialysis patients. Renal Fail 2003;25:569–578.
  • Lakshminrusimha S, Mathew B, Leach CL. Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide. Semin Perinatol 2016;40:160–173.
  • Gonzalvo R, Marti-Sistac O, Blanch L, Lopez-Aguilar J. Bench-to-bedside review: brain-lung interaction in the critically ill–a pending issue revisited. Crit Care (London, Engl) 2007;11:216.
  • Park SL, Won SY, Song JH, et al. EPO gene expression promotes proliferation, migration and invasion via the p38MAPK/AP-1/MMP-9 pathway by p21WAF1 expression in vascular smooth muscle cells. Cell Signal 2015;27:470–478.
  • Lu KY, Ching LC, Su KH, et al. Erythropoietin suppresses the formation of macrophage foam cells: role of liver X receptor alpha. Circulation 2010;121:1828–1837.
  • Desai A, Zhao Y, Lankford HA, Warren JS. Nitric oxide suppresses EPO-induced monocyte chemoattractant protein-1 in endothelial cells: implications for atherogenesis in chronic renal disease. Lab Invest J Tech Methods Pathol 2006;86:369–379.
  • Shiekh GA, Ayub T, Khan SN, Dar R, Andrabi KI. Reduced nitrate level in individuals with hypertension and diabetes J Cardiovasc Dis Res 2011;2:172–176.
  • Sag AA, Sos TA, Benli C, et al. Atherosclerotic renal artery stenosis in the post-CORAL era part 2: new directions in transcatheter nephron salvage following flawed revascularization trials. JASH 2016;10:368–377.
  • Piuhola J, Kerkela R, Keenan JI, et al. Direct cardiac actions of erythropoietin (EPO): effects on cardiac contractility, BNP secretion and ischaemia/reperfusion injury. Cli Sci (Lond, Engl 1979) 2008;114:293–304.
  • Porat O, Neumann D, Zamir O, et al. Erythropoietin stimulates atrial natriuretic peptide secretion from adult rat cardiac atrium. J Pharmacol Exp Ther 1996;276:1162–1168.
  • Kokot F, Wiecek A, Schmidt-Gayk H, et al. Influence of long-term erythropoietin therapy on endocrine abnormalities in haemodialyzed patients. Przeglad lekarski 1992;49:43–49.
  • Kokot F, Wiecek A, Schmidt-Gayk H, et al. Function of endocrine organs in hemodialyzed patients of long-term erythropoietin therapy. Artif Organs 1995;19:428–435.
  • Lai KN, Lui SF, Leung JC, et al. Effect of subcutaneous and intraperitoneal administration of recombinant human erythropoietin on blood pressure and vasoactive hormones in patients on continuous ambulatory peritoneal dialysis. Nephron 1991;57:394–400.
  • Lebel M, Kingma I, Grose JH, Langlois S. Hemodynamic and hormonal changes during erythropoietin therapy in hemodialysis patients. JASN 1998;9:97–104.
  • Rodrigue ME, Moreau C, Lariviere R, Lebel M. Relationship between eicosanoids and endothelin-1 in the pathogenesis of erythropoietin-induced hypertension in uremic rats. J Cardiovasc Pharmacol 2003; 41:388–395.
  • Glaus TM, Grenacher B, Koch D, et al. Gassmann, High altitude training of dogs results in elevated erythropoietin and endothelin-1 serum levels, Comparative biochemistry and physiology. Part A Mol Integr Physiol 2004;138:355–361.
  • Carlini R, Obialo CI, Rothstein M. Intravenous erythropoietin (rHuEPO) administration increases plasma endothelin and blood pressure in hemodialysis patients. Am J Hypertens 1993;6:103–107.
  • Kanbay M, Akcay A, Delibasi T, et al. Comparison of effects of darbepoetin alfa and epoetin alfa on serum endothelin level and blood pressure. Adv Therapy 2007;24:346–352.
  • Lebel M, Moreau V, Grose JH, et al. Plasma and peritoneal endothelin levels and blood pressure in CAPD patients with or without erythropoietin replacement therapy. Clin Nephrol 1998;49:313–318.
  • Stefanidis I, Mertens PR, Wurth P, et al. Influence of recombinant human erythropoietin therapy on plasma endothelin-1 levels during hemodialysis. Int J Artif Organs 2001;24:367–373.
  • Concas V, Laurent S, Brisac AM, et al. Endothelin has potent direct inotropic and chronotropic effects in cultured heart cells. J Hypertens Suppl Off J Int Soc Hypertens 19897;7:S96–S97.
  • Musialek P, Lei M, Brown HF, et al. Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, I(f). Circ Res 1997;81:60–68.
  • Naito M, Kawashima A, Akiba T, et al. Effects of an angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitors on burst forming units-erythroid in chronic hemodialysis patients. Am J Nephrol 2003;23:287–293.
  • Freudenthaler SM, Lucht I, Schenk T, et al. Dose-dependent effect of angiotensin II on human erythropoietin production. Pflugers Archiv Eur J Physiol 2000;439:838–844.
  • Brier ME, Bunke CM, et al. Erythropoietin-induced antinatriuresis mediated by angiotensin II in perfused kidneys. JASN 1993;3:1583–1590.
  • Naomi S, Umeda T, Iwaoka T, et al. Endogenous erythropoietin and salt sensitivity of blood pressure in patients with essential hypertension Am J Hypertens 1993;6:15–20.
  • Malik U, Raizada V. Some aspects of the renin-angiotensin-system in hemodialysis patients. Kidney Blood Pressure Res 2015;40:614–622.
  • Okura Y, Oshima T, Yasunobu Y, et al. Effect of erythropoietin treatment on blood pressure and intracellular cation concentrations in maintenance hemodialysis patients. Hypertens Res Off J Jpn Soc Hypertens 1996;19:91–95.
  • Boyle SM, Berns JS. Erythropoietin and resistant hypertension in CKD. Semin Nephrol 2014;34:540–549.
  • Ono K, Hisasue Y. The rate of increase in hematocrit, humoral vasoactive substances and blood pressure changes in hemodialysis patients treated with recombinant human erythropoietin or blood transfusion. Clin Nephrol 1992;37:23–27.
  • Poux JM, Lartigue M, Chaisemartin RA, et al. Uraemia is necessary for erythropoietin-induced hypertension in rats. Clin Exp Pharmacol Physiol 1995;22:769–771.
  • Garcia-Garcia F, Krueger JM. Intracerebroventricular injection of erythropoietin enhances sleep in the rat. Brain Res Bull 2003;61:541–546.
  • Engel A, Pagel H. Increased production of erythropoietin after application of antidiuretic hormone. A consequence of renal vasoconstriction? Exp Clin Endocrinol Diabetes Off J Ger Soci Endocrinol Ger Diabetes Assoc 1995;103:303–307.
  • Marcinkowski W, Zhang G, Smogorzewski M, Massry SG. Elevation of [Ca2+]i of renal proximal tubular cells and down-regulation of mRNA of PTH-PTHrP, V1a and AT1 receptors in kidney of diabetic rats. Kidney Int 1997;51:1950–1955.
  • Horiguchi H, Oguma E, Kayama F. Cadmium and cisplatin damage erythropoietin-producing proximal renal tubular cells. Arch Toxicol 2006;80:680–686.
  • Zhou XJ, Pandian D, Wang XQ, Vaziri ND. Erythropoietin-induced hypertension in rat is not mediated by alterations of plasma endothelin, vasopressin, or atrial natriuretic peptide levels. JASN 1997;8:901–905.
  • D’Amico M, Berrino L, Filippelli A, et al. Relation between L-arginine-nitric oxide pathway and endothelin-1 effects in periaqueductal gray area of rats. J Cardiovasc Pharmacol 1994;24:974–978.
  • Matsumura K, Abe I, Tsuchihashi T, et al. Central effect of endothelin on neurohormonal responses in conscious rabbits. Hypertension 1991;17:1192–1196.
  • Ditting T, Hilgers KF, Stetter A, et al. Renal sympathetic nerves modulate erythropoietin plasma levels after transient hemorrhage in rats. Am J Physiol Renal Physiol 2007;293:F1099–1106.
  • Fink GD, Paulo LG, Fisher JW. Effects of beta adrenergic blocking agents on erythropoietin production in rabbits exposed to hypoxia. J Pharmacol Exp Ther 1975;193:176–181.
  • Muller R, Steffen HM, Brunner R, et al. Disordered alpha 2-adrenoreceptor function in hemodialysis patients with renal anemia–a possible cause of increased blood pressure in relation to recombinant human erythropoietin? Klinische Wochenschrift 1991;69:742–748.
  • Bockman CS, Jeffries WB, Abel PW. Binding and functional characterization of alpha-2 adrenergic receptor subtypes on pig vascular endothelium. J Pharmacol Exp Ther 1993;267:1126–1133.
  • Sanchis-Gomar F, Garcia-Gimenez JL, Pareja-Galeano H, et al. Erythropoietin and the heart: physiological effects and the therapeutic perspective. Int J Cardiol 2014;171:116–125.
  • Tekin D, Dursun AD, Xi L. Hypoxia inducible factor 1 (HIF-1) and cardioprotection. Acta Pharmacol Sinica 2010;31:1085–1094.
  • Mudalagiri NR, Mocanu MM, Di Salvo C, et al. Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation. Br J Pharmacol 2008;153:50–56.
  • Liu X, Xie W, Liu P, et al. Mechanism of the cardioprotection of rhEPO pretreatment on suppressing the inflammatory response in ischemia-reperfusion. Life Sci 2006;78:2255–2264.
  • Wen Y, Ma YX, Zhang XJ, et al. Erythropoietin inhibits angiotensin II induced cardiomyocyte hypertrophy in vitro via activating PI3K/Akt-eNOS pathway. Zhonghua xin xue guan bing za zhi 2009;37:436–440.
  • Talan MI, Latini R. Myocardial infarction: cardioprotection by erythropoietin. Methods Mol Biol (Clifton, NJ) 2013;982:265–302.
  • Xanthos T, Vasileiou PV, Kakavas S, et al. The potential role of erythropoietin as a pleiotropic agent in post-cardiac arrest syndrome. Curr Pharm Des 2011;17:1517–1529.
  • Latini R, Brines M, Fiordaliso F. Do non-hemopoietic effects of erythropoietin play a beneficial role in heart failure?. Heart Fail Rev 2008;13:415–423.
  • Krause KT, Jaquet K, Geidel S, et al. Percutaneous endocardial injection of erythropoietin: assessment of cardioprotection by electromechanical mapping Eur J Heart Fail 2006;8:443–450.
  • Hirata A, Minamino T, Asanuma H, et al. Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts. Cardiovasc Drugs Therapy/Sponsored by the International Society of Cardiovascular Pharmacotherapy 2005;19:33–40.
  • Dame C. GATA4: the missing link between Epo and cardioprotection?! NMCD 2013;23:e19–e20.
  • Shan X, Xu X, Cao B, et al. Transcription factor GATA-4 is involved in erythropoietin-induced cardioprotection against myocardial ischemia/reperfusion injury. Int J Cardiol 2009;134:384–392.
  • Ghaboura N, Tamareille S, Ducluzeau PH, et al. Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3beta signaling. Basic Res Cardiol 2011;106:147–162.
  • Bahlmann FH, Kielstein JT, Haller H, Fliser D, Erythropoietin and progression of CKD. Kidney Int 2007;(Supplement):S21–S25.
  • Bahlmann FH, Song R, Boehm SM, et al. Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure, Circulation 110 (2004):1006–1012.
  • Logar CM, Brinkkoetter PT, Krofft RD, et al. Darbepoetin alfa protects podocytes from apoptosis in vitro and in vivo. Kidney Int 2007;72:489–498.
  • Eto N, Wada T, Inagi R, et al. Podocyte protection by darbepoetin: preservation of the cytoskeleton and nephrin expression. Kidney Int 2007;72:455–463.
  • Bi B, Guo J, Marlier A, et al. Erythropoietin expands a stromal cell population that can mediate renoprotection. Am J Physiol Renal Physiol 2008;295:F1017–1022.
  • Breggia AC, Wojchowski DM, Himmelfarb J. JAK2/Y343/STAT5 signaling axis is required for erythropoietin-mediated protection against ischemic injury in primary renal tubular epithelial cells. Am J Physiol Renal Physiol 2008;295:F1689–F1695.
  • Johnson DW, Pat B, Vesey DA, et al. Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure Kidney Int 2006;69:1806–1813.
  • Chattong S, Tanamai J, Kiatsomchai P, et al. Glutaraldehyde erythropoietin protects kidney in ischaemia/reperfusion injury without increasing red blood cell production. Br J Pharmacol 2013;168:189–199.
  • van Rijt WG, van Goor H, Ploeg RJ, Leuvenink HG. Erythropoietin-mediated protection in kidney transplantation: nonerythropoietic EPO derivatives improve function without increasing risk of cardiovascular events. Transplant Int Off J Eur Soc Organ Transplant 2014;27:241–248.
  • Stoyanoff TR, Todaro JS, Aguirre MV, et al. Amelioration of lipopolysaccharide-induced acute kidney injury by erythropoietin: involvement of mitochondria-regulated apoptosis. Toxicology 2014;318:13–21.
  • Gobe GC, Bennett NC, West M, et al. Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury. Am J Physiol Renal Physiol 2014;306:F681–692.
  • Yamaleyeva LM, Guimaraes-Souza NK, Krane LS, et al. Cell therapy with human renal cell cultures containing erythropoietin-positive cells improves chronic kidney injury. Stem Cells Transl Med 2012;1:373–383.
  • Bernaudin M, Bellail A, Marti HH, et al. Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia 2000;30271–278.
  • Parra AL, Rodriguez JC. Nasal neuro EPO could be a reliable choice for neuroprotective stroke treatment. Cent Nerv Syst Agents Med Chem 2012;12:60–68.
  • Gao Y, Mengana Y, Cruz YR, et al. Different expression patterns of Ngb and EPOR in the cerebral cortex and hippocampus revealed distinctive therapeutic effects of intranasal delivery of Neuro-EPO for ischemic insults to the gerbil brain. J Histochem Cytochem Off J Histochem Soc 2011;59:214–227.
  • Schober ME, Block B, Beachy JC, et al. Early and sustained increase in the expression of hippocampal IGF-1, but not EPO, in a developmental rodent model of traumatic brain injury. J Neurotrauma 2010;27:2011–2020.
  • Shen J, Wu Y, Xu JY, et al. ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD. Invest Ophthalmol Visual Sci 2010;51:35–46.
  • Nichol A, French C, Little L, et al. Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial. Lancet (Lond Engl) 2015;386:2499–2506.
  • Menon DK, Maas AI. EPO in traumatic brain injury: two strikes…but not out? Lancet (Lond, Engl) 2015;386:2452–2454.
  • Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med (Cambridge, Mass.) 2002;8:495–505.
  • Ehrenreich H, Weissenborn K, Prange H, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke J Cereb Circ 2009;40:e647–656.
  • Minnerup J, Wersching H, Schabitz WR. EPO for stroke therapy - Is there a future for further clinical development? Exp Transl Stroke Med 2010;2:10.
  • Chi OZ, Hunter C, Liu X, Weiss HR. Effects of erythropoietin on blood-brain barrier disruption in focal cerebral ischemia. Pharmacology 2008;82:38–42.
  • Wang R, Wu X, Liang J, et al. Intra-artery infusion of recombinant human erythropoietin reduces blood-brain barrier disruption in rats following cerebral ischemia and reperfusion. Int J Neurosc 2015;125:693–702.
  • Bahcekapili N, Uzum G, Gokkusu C, et al. The relationship between erythropoietin pretreatment with blood-brain barrier and lipid peroxidation after ischemia/reperfusion in rats. Life Sci 2007;80:1245–1251.
  • Chu H, Ding H, Tang Y, Dong Q. Erythropoietin protects against hemorrhagic blood-brain barrier disruption through the effects of aquaporin-4. Lab Invest J Tech Methods Pathol 2014;94:1042–1053.
  • Uzum G, Sarper Diler A, Bahcekapili N, Ziya Ziylan Y. Erythropoietin prevents the increase in blood-brain barrier permeability during pentylentetrazol induced seizures. Life Sci 2006;78:2571–2576.
  • Martinez-Estrada OM, Rodriguez-Millan E, Gonzalez-De Vicente E, et al. Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability. Eur J Neurosci 2003;18:2538–2544.
  • Banks WA, Jumbe NL, Farrell CL, et al. Passage of erythropoietic agents across the blood-brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa. Eur J Pharmacol 2004;505:93–101.
  • Xenocostas A, Cheung WK, Farrell F, et al. The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin. Eur J Clin Pharmacol 2005;61:189–195.
  • Merelli A, Caltana L, Girimonti P, et al. Recovery of motor spontaneous activity after intranasal delivery of human recombinant erythropoietin in a focal brain hypoxia model induced by CoCl2 in rats. Neurotoxicity Res 2011;20:182–192.
  • Rahimi Nedjat M, Wahmann M, Bachli H, et al. Erythropoietin neuroprotection is enhanced by direct cortical application following subdural blood evacuation in a rat model of acute subdural hematoma. Neuroscience 2013;238:125–134.
  • Xue YQ, Ma BF, Zhao LR, et al. AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson’s disease. Gene Therapy 2010;17:83–94.
  • Boado RJ, Hui EK, Lu JZ, Pardridge WM. Drug targeting of erythropoietin across the primate blood-brain barrier with an IgG molecular Trojan horse. J Pharmacol Exp Ther 2010;333:961–969.
  • Zhang F, Xing J, Liou AK, et al. Enhanced delivery of erythropoietin across the blood-brain barrier for neuroprotection against ischemic neuronal injury. Transl Stroke Res 2010;1:113–121.
  • Li X, Hassoun HT, Santora R, Rabb H. Organ crosstalk: the role of the kidney. Curr Opin Crit Care 2009;15:481–487.
  • Wohlauer MV, Sauaia A, Moore EE, et al. Acute kidney injury and posttrauma multiple organ failure: the canary in the coal mine J Trauma Acute Care Surgery 2012;72:373–378; discussion 379–380.
  • Janssens U, Joannidis M. Acute cardiorenal syndromes. Medizinische Klinik Intensivmedizin und Notfallmedizin 2016;111:341–358.
  • Kingma JG Jr., Simard D, Rouleau JR. Renocardiac syndromes: physiopathology and treatment stratagems. Can J Kidney Health Disease 2015;2:41.
  • Cho E, Kim M, Ko YS, et al. Role of inflammation in the pathogenesis of cardiorenal syndrome in a rat myocardial infarction model. Nephrol Dialysis transpl Off Publ Eur Dialysis Transpl Assoc Eur Renal Assoc 2013;28:2766–2778.
  • Virzi G., Day S, de Cal M, et al. Heart-kidney crosstalk and role of humoral signaling in critical illness. Crit Care (Lond, Engl) 2014;18:201.
  • Schroten NF, Gaillard CA, van Veldhuisen DJ, et al. New roles for renin and prorenin in heart failure and cardiorenal crosstalk. Heart Fail Rev 2012;17:191–201.
  • Kato J, Nakayama M, Zhu WJ, et al. Ischemia/reperfusion of unilateral kidney exaggerates aging-induced damage to the heart and contralateral kidney. Nephron Exp Nephrol 2014;126:183–190.
  • Jahng JW, Song E, Sweeney G. Crosstalk between the heart and peripheral organs in heart failure. Exp Mol Med 2016;48:e217.
  • Husain-Syed F, McCullough PA, Birk HW, et al. Cardio-Pulmonary-Renal Interactions: a multidisciplinary approach. J Am Coll Cardiol 2015;65:2433–2448.
  • Ma S, Zhao H, Ji X, Luo Y. Peripheral to central: organ interactions in stroke pathophysiology. Exp Neurol 2015;272:41–49.
  • Gonzales-Portillo C, Ishikawa H, et al. Stroke and cardiac cell death: Two peas in a pod. Clin Neurol Neurosurgery 2016;142:145–147.
  • Mazzeo AT, Micalizzi A, Mascia L, et al. Brain-heart crosstalk: the many faces of stress-related cardiomyopathy syndromes in anaesthesia and intensive care. Br J Anaesthesia 112 (2014):803–815.
  • Quilez ME, Lopez-Aguilar J, Blanch L. Organ crosstalk during acute lung injury, acute respiratory distress syndrome, and mechanical ventilation. Curr Opin Crit Care 2012;18:23–28.
  • Rodriguez-Gonzalez R, Ramos-Nuez A, et al. Endotoxin-induced lung alveolar cell injury causes brain cell damage. Exp Biol Med (Maywood, N.J.) 2015;240:135–142.
  • Mazzeo AT, Fanelli V, Mascia L. Brain-lung crosstalk in critical care: how protective mechanical ventilation can affect the brain homeostasis. Minerva Anestesiol 2013;79:299–309.
  • Lopez-Aguilar J, Blanch L. Brain injury requires lung protection. Ann Transl Med 2015;3:S5.
  • Pelosi P, Rocco PR. The lung and the brain: a dangerous cross-talk. Crit Care (Lond, Engl) 2011;15:168.
  • Nongnuch A, Panorchan K, Davenport A. Brain-kidney crosstalk. Crit Care (Lond, Engl) 2014;18:225.
  • Oba T, Yasukawa H, Nagata T, et al. Renal nerve-mediated erythropoietin release confers cardioprotection during remote ischemic preconditioning. Circ J Off J Jpn Circ Soc 2015;79:1557–1567.
  • Ogino A, Takemura G, Kawasaki M, et al. Erythropoietin receptor signaling mitigates renal dysfunction-associated heart failure by mechanisms unrelated to relief of anemia. J Am Coll Cardiol 2010;56:1949–1958.
  • Rocha J, Eduardo-Figueira M, et al. Erythropoietin reduces acute lung injury and multiple organ failure/dysfunction associated to a scald-burn inflammatory injury in the rat. Inflammation 2015;38:312–326.
  • Korkmaz T, Kahramansoy N, Kilicgun A, Firat T. The effect of erythropoietin to pulmonary injury and mast cells secondary to acute pancreatitis. BMC Res Notes 2014;7:267.
  • Moeini M, Nematbakhsh M, et al. Protective role of recombinant human erythropoietin in kidney and lung injury following renal bilateral ischemia-reperfusion in rat model. Int J Preventive Med 2013;4:648–655.
  • Ardalan MR, Estakhri R, et al. Erythropoietin ameliorates oxidative stress and tissue injury following renal ischemia/reperfusion in rat kidney and lung. Med Principles Pract Int J Kuwait Univ Health Sci Centre 2013;22:70–74.
  • Bari MA, Rahman MA. Effect of iron deficiency anemia on the development of atherosclerosis in chicks. Atherosclerosis 1975;21:401–408.
  • Kessler P, Veberova J, Bradackova I. Occurrence of diabetes, hyperinsulinism and other risk factors for atherosclerosis in patients with pernicious anemia. Vnitrni lekarstvi 1998;44:222–226.
  • Gursel O, Kurekci AE, Tascilar E, et al. Premature atherosclerosis in children with beta-thalassemia major. J Pediatric Hematol/Oncol 2012;34:630–634.
  • Remacha AF, Bellido M, Garcia-Die F, et al. Serum erythropoietin and erythroid activity in vitamin B12 deficiency. Haematologica 1997;82:67–68.
  • Vedovato M, Salvatorelli G, Taddei Masieri M, Vullo C. Epo serum levels in heterozygous beta-thalassemia. Haematologia 1993;25:19–24.
  • Xue CE, Shen QH, Wang Y, et al. Clinical significance of the serum EPO level in patients with iron deficiency anemia, Zhongguo shi yan xue ye xue za zhi/Zhongguo bing li sheng li xue hui = J Exp Hematol/Chin Assoc Pathophysiol 2015;23:1410–1414.
  • d’Uscio LV, Smith LA, Santhanam AV, et al. Essential role of endothelial nitric oxide synthase in vascular effects of erythropoietin. Hypertension 2007;49:1142–1148.
  • Weissmann N, Manz D, Buchspies D, et al. Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia. Thromb Haemost 2005;94:630–638.
  • Satoh K, Kagaya Y, Nakano M, et al. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 2006;113:1442–1450.
  • Kuriyama S, Morio Y, Toba M, et al. Genistein attenuates hypoxic pulmonary hypertension via enhanced nitric oxide signaling and the erythropoietin system, American journal of physiology. Lung Cell Mol Physiol 2014;306:L996–l1005.
  • Ikarashi N, Toba K, Kato K, et al. Erythropoietin, but not asialoerythropoietin or carbamyl-erythropoietin, attenuates monocrotaline-induced pulmonary hypertension in rats. Clin Exp Hypertens (New York, NY: 1993) 2012;34:575–581.
  • van Albada ME, du Marchie Sarvaas GJ, Koster J, et al. Effects of erythropoietin on advanced pulmonary vascular remodelling. Eur Respir J 2008;31:126–134.
  • Underwood CF, Hildreth CM, Wyse BF, et al. Uraemia: an unrecognized driver of central neurohumoral dysfunction in chronic kidney disease? Acta Physiol (Oxford, Engl) 2016.
  • Tepel M. Oxidative stress: does it play a role in the genesis of essential hypertension and hypertension of uraemia? Nephrol Dialysis Transpl Off Publ Eur Dialysis Transplant Asso Eur Renal Assoc 2003;18:1439–1442.
  • Sarkar SR, Kaitwatcharachai C, Levin NW. Nitric oxide and hemodialysis. Semin Dialysis 2004;17:224–228.
  • Cirillo M, Laurenzi M, Trevisan M, Stamler J. Hematocrit, blood pressure, and hypertension. The Gubbio Population Study. Hypertension 1992;20:319–326.
  • Goubali A, Voukiklaris G, Kritsikis S, et al. Relation of hematocrit values to coronary heart disease, arterial hypertension, and respiratory impairment in occupational and population groups of the Athens area. Angiology 1995;46:719–725.
  • Liu X, Liang J, Qiu Q, et al. Association of hematocrit and pre-hypertension among Chinese adults: the CRC study. Cell Biochem Biophys 2015;71:1123–1128.
  • Nakanishi N, Yoshida H, Okamoto M, et al. Hematocrit and risk for hypertension in middle-aged Japanese male office workers. Ind Health 2001;39:17–20.
  • Strand A, Gudmundsdottir H, Hoieggen A, et al. Increased hematocrit before blood pressure in men who develop hypertension over 20 years. JASH 2007;1:400–406.
  • Lebel M, Grose JH, Blais R. Increased hematocrit with normal red blood cell mass in early borderline essential hypertension. Clin Exp Hypertens Part A Theory Pract 1989;11:1505–1514.
  • Sasagawa I, Nakada T, Hashimoto T, et al. Change in haemoglobin concentration, haematocrit and vasoactive hormones in haemodialysis patients with erythropoietin-associated hypertension. Int Urol Nephrol 1994;26:237–243.
  • Steffen HM, Brunner R, Muller R, et al. Peripheral hemodynamics, blood viscosity, and the renin-angiotensin system in hemodialysis patients under therapy with recombinant human erythropoietin. Contrib Nephrol 1989;76:292–298.
  • Verbeelen D, Bossuyt A, Smitz J, et al. Hemodynamics of patients with renal failure treated with recombinant human erythropoietin Clin Nephrol 1989;31:6–11.
  • Vlahakos DV, Balodimos C, Papachristopoulos V, et al. Renin-angiotensin system stimulates erythropoietin secretion in chronic hemodialysis patients. Clin Nephrol 1995;43:53–59.
  • Yaqoob M, Morris K, Bell GM, Ahmad R. Suppression of the renin-angiotensin-aldosterone axis with erythropoietin therapy by a negative feedback loop. Nephrol Dialysis Transplant Off Publ Eur Dialysis Transplant Assoc Eur Renal Assoc 1992;7:125–128.
  • Hori K, Onoyama K, Iseki K, et al. Hemodynamic and volume changes by recombinant human erythropoietin (rHuEPO) in the treatment of anemic hemodialysis patients. Clin Nephrol 1990;33:293–298.
  • Selcuk Y, San A, Sahin M. Effects of treatment with recombinant human erythropoietin on hemodynamic functions and vasoactive hormones in renal anemia. Tr J Med Sci 1994;22:271–275.
  • Yeksan M, Tamer N, Turk S. Hemodynamic changes with recombinant human erythropoietin therapy in uremic hemodialyzed patients. Tr J of Med Sci 1994;20:173–178.
  • Jandeleit K, Ehmer B, Heintz B, et al. Hormonal and electrolyte changes under regular therapy with recombinant human erythropoietin in hemodialysis patients. Contrib Nephrol 1991;91:57–60.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.