Differential Effects of Low-Dose Erythropoietin in Rat Model of Diabetic Nephropathy Submitted: Jan 3, 2018 Accepted: Feb 26, 2018 Published online: Mar 3, 2018

##plugins.themes.bootstrap3.article.main##

Abdel-Motaal Fouda Rehab H. Ashour Farida El-Banna Mohamed A. Saad Fatma A. Mostafa Manal I. Fouda

Abstract

Background. Previous reports on the renoprotective effect of erythropoietin (EPO) in the setting of chronic kidney disease (CKD) have yielded conflicting results. The aim of this study is to clarify the effect of low, non-hematopoietic dose of EPO on the evolution of diabetic nephropathy (DN) in rat model. Methods. Low dose of recombinant human EPO (150 U/kg, s.c. three times/week) was given to streptozotocin (STZ)-induced diabetic rats in two schedules; in the first one, EPO was given from day 2 after STZ injection till the end of the study (28 weeks) as prophylactic treatment; and in the other schedule EPO was given after development of DN (last 8 weeks) as therapeutic treatment. Albuminuria, blood pressure, creatinine clearance, renal venous oxygen tension (vPO2), plasma EPO, hematocrit and renal histopathology were assessed. Results. Unexpectedly, 28 weeks administration of EPO to diabetic rats led to aggravation of albuminuria and worsening of histopathological damage in spite of partial correction of renal hypoxia. Contrary to this, terminal 8 weeks EPO therapy of DN reduced albuminuria and demonstrated some favorable effects on biochemical changes and histologic picture. Conclusion. Low dose EPO exerted differential effects in rat model of DN according to treatment duration. In addition, findings of the present study warrants further investigations of the exact renoprotective role of EPO in diabetic patients with CKD who receive EPO therapy for long periods.

Downloads

Download data is not yet available.

##plugins.themes.bootstrap3.article.details##

Keywords

Erythropoietin, Diabetic nephropathy, Renal hypoxia, Albuminuria

How to Cite
Fouda, A.-M. ., Ashour, R. H. ., El-Banna, F. ., Saad, M. A. ., Mostafa, F. A. ., & Fouda, M. I. . (2018). Differential Effects of Low-Dose Erythropoietin in Rat Model of Diabetic Nephropathy: Submitted: Jan 3, 2018 Accepted: Feb 26, 2018 Published online: Mar 3, 2018. Advances in Medicine and Medical Research, 1(1), 25–33. https://doi.org/10.31377/ammr.v1i1.494
Section
Original Articles
Author Biography

Abdel-Motaal Fouda, Department of Clinical Pharmacology, Mansoura University Faculty of Medicine, Mansoura 35516, Egypt

envelope-1-5121.png

Corresponding Author:

Email: foudaamm@mans.edu.eg Tel: 00201113974766

References

Martínez-Castelao A, Navarro-González J, Górriz J, de Alvaro F. The Concept and the epidemiology of diabetic nephropathy have changed in recent years. J Clin Med. 2015;4(6):1207-1216.

Vinod PB. Pathophysiology of diabetic nephropathy. Clin Queries Nephrol. 2012;1(2):121-126.

Heyman SN, Khamaisi M, Rosen S, Rosenberger C. Renal parenchymal hypoxia, hypoxia response and the progression of chronic kidney disease. Am J Nephrol. 2008;28(6):998-1006.

Fisher JW. Erythropoietin: Physiology and Pharmacology Update 2. Exp Biol Med. 2003;228(1):1-14.

Konstantinopoulos PA, Karamouzis M V, Papavassiliou AG. Selective modulation of the erythropoietic and tissue-protective effects of erythropoietin: time to reach the full therapeutic potential of erythropoietin. Biochim Biophys Acta (BBA)-Reviews Cancer. 2007;1776(1):1-9.

Tahamtan, M., Moosavi, S. M.S., Sheibani, V., Nayebpour, M., Esmaeili-Mahani, S. and Shabani, M. Erythropoietin attenuates motor impairments induced by bilateral renal ischemia/reperfusion in rats. Fundam Clin Pharmacol, 2016; 30:502–510.

Bahlmann F, Kielstein J, Haller H, Fliser D. Erythropoietin and progression of CKD. Kidney Int, 2007;72:S21-S25.

Johnson D. Prevention of progression of kidney disease. Nephrology. 2006;11:S2-S197.

Menne J, Park J-K, Shushakova N, Mengel M, Meier M, Fliser D. The continuous erythropoietin receptor activator affects different pathways of diabetic renal injury. J Am Soc Nephrol. 2007;18(7):2046-2053.

Toba H, Sawai N, Morishita M, Murata S, Yoshida M, Nakashima K, Morita Y, Kobara M, Nakata T. Chronic treatment with recombinant human erythropoietin exerts renoprotective effects beyond hematopoiesis in streptozotocin- induced diabetic rat. Eur J Pharmacol. 2009;612(1):106-114.

Furman BL. Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol. 2015;70:5.47.1-20

Gross ML, Ritz E, Schoof A, Adamczak M, Koch A, Tulp O, Parkman A, El-Shakmak A, Szabo A, Amann K. Comparison of renal morphology in the streptozotocin and the SHR/N-cp models of diabetes. Lab Investig. 2004;84(4):452.
.
Fliser D, Bahlmann FH, Haller H. EPO: renoprotection beyond anemia correction. Pediatr Nephrol. 2006;21(12):1785-1789.

Rasmussen P, Kim YS, Krogh-Madsen R, Lundby C, Olsen NV, Secher NH, van Lieshout JJ. Both acute and prolonged administration of EPO reduce cerebral and systemic vascular conductance in humans. FASEB J. 2012;26(3):1343-1348.

Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G. Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. “Gruppo italiano di studi epidemiologici in nefrologia” (gisen). Kidney Int. 1998; 53:1209–1216.

Gretz N, Lasserre J, Kraft K, Waldherr R, Weidler B, Meisisnger E, Strauch M. Efficacy and side effects of erythropoietin used in the treatment of anemia of uremic rats. Contr Nephrol. 1987; 60:236–44.

Provatopoulou ST, Ziroyiannis PN. Clinical use of erythropoietin in chronic kidney disease: outcomes and future prospects. Hippokratia. 2011; 15(2): 109–115.

Lasne F, Martin L, Crepin N, de Ceaurriz J. Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones. Anal Biochem. 2002;311(2):119-126.

Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA). Clin J Am Soc Nephrol 2009; 4:470.
.
Panzacchi G, Pieruzzi F, Castoldi G, Busca G, Bolla GB, Buccianti G, Radice F, Fava C, Martini I, Zanchetti A, Golin Fouda et al. 2018Erythropoietin and diabetic nephropathy

R, Stella A. Effects of erythropoietin administration on blood pressure and urinary albumin excretion in rats. Am J Hypertens. 1997;10(7):772-778.

Bode-Böger SM, Böger RH, Kuhn M, Radermacher J, Frölich JC. Recombinant human erythropoietin enhances vasoconstrictor tone via endothelin-1 and constrictor prostanoids. Kidney Int. 1996;50(4):1255-1261.

Tomohiro T, Kumai T, Sato T, Takeba Y, Kobayashi S, Kimura K. Hypertension aggravates glomerular dysfunction with oxidative stress in a rat model of diabetic nephropathy. Life Sci. 2007;80(15):1364-1372.

Fine LG, Bandyopadhay D, Norman JT. Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int. 2000;57:S22-S26.

Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007;117(12):3810.

Palm F, Nordquist L. Renal tubulointerstitial hypoxia: cause and consequence of kidney dysfunction. Clin Exp Pharmacol Physiol. 2011;38(7):474-480.

Friederich-Persson M, Thorn E, Hansell P, Nangaku M, Levin M, Palm F. Kidney Hypoxia, Attributable to Increased Oxygen Consumption, Induces Nephropathy Independently of Hyperglycemia and Oxidative Stress. Hypertension. 2013;62(5):914-919.

El-Khatib MT. The role of inflammation on iron and erythropoietin resistance. J Nephrol Renal Transplant. 2009;2(2):45-54.

Bamgbola OF. Pattern of resistance to erythropoietin-stimulating agents in chronic kidney disease. Kidney Int. 2011;80(5):464-474.

Navarro JF, Mora C. Diabetes, inflammation, proinflammatory cytokines, and diabetic nephropathy. Sci World J. 2006;6:908-917.

Hu X, Zhang X, Jin G, Shi Z, Sun W1, Chen F. Geniposide reduces development of streptozotocin-induced diabetic nephropathy via regulating nuclear factor-kappa B signaling
pathways. Fundam Clin Pharmacol. 2017;31(1):54-63.

Macdougall IC, Cooper A. The inflammatory response and epoetin sensitivity. Nephrol Dial Transplant. 2002;17(1):48-52.

Macdougall IC, Cooper AC. Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant. 2002;17(11):39-43.

Ali MA, Heeba GH, El-Sheikh AK. Modulation of heme oxygenase-1 expression and activity affects streptozotocin-induced diabetic nephropathy in rats. Fundam Clin Pharmacol. 2017;31(5):546-557.

Gallucci MT, Lubrano R, Meloni C, Morosetti M, Manca di Villahermosa S, Scoppi P, Palombo G, Castello MA, Casciani CU. Red blood cell membrane lipid peroxidation and resistance to erythropoietin therapy in hemodialysis patients. Clin Nephrol. 1999;52(4):239-245