Abstract
The purpose of the work was to investigate mechanisms of erythropoietin-induced protection and accelerated recovery of kidneys and ureters from obstructive injury. Unilateral ureteral obstruction was established for 24, 48, and 72 h in C57BL/6 mice using a non-traumatic micro-clip followed by the microscopic quantification of ureteral peristalsis pre- and post-obstruction. Expression of erythropoietin, erythropoietin receptor, β-common receptor, and downstream apoptosis-related markers was assessed by RT-PCR and immunohistochemistry in ureters and kidneys and compared to the respective organs on the contralateral side within each animal. Expression of genes in kidneys and ureters from mice treated with 20 IU of erythropoietin daily for 72 h prior to obstruction was compared to that of untreated mice following obstruction. Apoptosis in ureteral tissues after 72-h obstruction was assessed via TUNEL assay. Ureteral obstruction increased apoptosis in affected ureters, with peristaltic function halted following all periods of obstruction. Erythropoietin treatment suppressed apoptosis in obstructed tissues and increased the percentage of mice retaining ureteral function immediately following obstruction reversal. Erythropoietin, erythropoietin receptor, Bcl-2, and Bcl-xl mRNA expression were down-regulated, while phospho-Nf-ĸb p65 was up-regulated in ureteral epithelia following obstruction. Erythropoietin treatment induced anti-apoptotic signaling via down-regulated Bax mRNA expression and abrogated phospho-Nf-ĸb p65. Erythropoietin-induced protection of ureteral function and accelerated recovery post-obstruction removal is mediated via anti-apoptotic mechanisms. Ureteral function is disrupted even following obstruction removal, negatively affecting renal function due to delayed recovery. Thus, our results represent a potential target for the development of safe therapeutic agents aimed at improving functional recovery from obstructive injury.
Similar content being viewed by others
References
Acikgoz Y, Can B, Bek K, Acikgoz A, Ozkaya O, Genc G, Sarikaya S (2014) The effect of simvastatin and erythropoietin on renal fibrosis in rats with unilateral ureteral obstruction. Ren Fail 36(2):252–257
Akiho H, Blennerhassett P, Deng Y, Collins SM (2002) Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 282(2):G22–G232
Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M et al (2004) Erythropoietin mediates tissue protection through an erythropoietin and common β-subunit heteroreceptor. Proc Natl Acad Sci U S A 101(41):14907–14912
Chang Y, Choi DE, Na K, Lee S, Suh K, Kim SY, Shin YT, Lee KW (2009) Erythropoietin attenuates renal injury in an experimental model of rat unilateral ureteral obstruction via anti-inflammatory and anti-apoptotic effects. J Urol 181(3):1434–1443
Chuang Y, Chuang W, Huang S, Huang C (2002) Over-expression of apoptosis-related proteins contributes to muscular damage in the obstructed ureter of the rat. BJU Int 89(1):106–112
Chuang Y, Chuang W, Huang C (2001) Myocyte apoptosis in the pathogenesis of ureteral damage in rats with obstructive uropathy. Urology 58(3):463–470
Chuang Y, Chuang W, Huang S, Liu C, Huang C (2009) Inhibition of nuclear factor-kappa B (NF-κB) activation attenuates ureteric damage in obstructive uropathy. Pharmacol Res 60(4):347–357
Dzietko M, Felderhoff-Mueser U, Sifringer M, Krutz B, Bittigau P, Thor F, Heumann R, Bührer C, Ikonomidou C, Hansen HH (2004) Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity. Neurobiol Dis 15(2):177–187
Fares F, Havron A, Fima E (2011, 2011) Designing a long acting erythropoietin by fusing three carboxyl-terminal peptides of human chorionic gonadotropin subunit to the N-terminal and C-terminal coding sequence. Int J Cell Biol
Ghezzi P, Brines M (2004) Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 11:S3–S44
Hegarty NJ, Young LS, Kirwan CN, O'Neill AJ, Bouchier-Hayes DM, Sweeney P, Watson RW, Fitzpatrick JM (2001) Nitric oxide in unilateral ureteral obstruction: effect on regional renal blood flow. Kidney Int 59(3):1059–1065
Janssen C, Buttyan R, Seow CY, Jäger W, Solomon D, Fazli L et al (2017) A role for the hedgehog effector Gli1 in mediating stent-induced ureteral smooth muscle dysfunction and aperistalsis. Urology 104(242):e-242–e-2e8
Janssen C, Jger W, Moskalev I, Fazli L, Throff JW, Lange D (2015) Erythropoietin accelerates the regeneration of ureteral function in a murine model of obstructive uropathy. J Urol 193(2):714–721
Jay AP, Nicol DL (2017) Chapter 3: The pathophysiology of upper tract obstruction. In Kulkarni R (ed) Ureteric Stenting, John Wiley & Sons Ltd, p 16–28
Johnson DW, Pat B, Vesey DA, Guan Z, Endre Z, Gobe GC (2006) Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure. Kidney Int 69(10):1806–1813
Kajbafzadeh A, Payabvash S, Salmasi AH, Monajemzadeh M, Tavangar SM (2006) Smooth muscle cell apoptosis and defective neural development in congenital ureteropelvic junction obstruction. J Urol 176(2):718–723
Kang HJ, Lee HY, Jin MH, Jeong HJ, Han SW (2009) Decreased interstitial cells of Cajal-like cells, possible cause of congenital refluxing megaureters: histopathologic differences in refluxing and obstructive megaureters. Urology 74(2):318–323
Kitamura H, Isaka Y, Takabatake Y, Imamura R, Suzuki C, Takahara S, Imai E (2008) Nonerythropoietic derivative of erythropoietin protects against tubulointerstitial injury in a unilateral ureteral obstruction model. Nephrol Dial Transplant 23(5):1521–1528
La Ferla K, Reimann C, Jelkmann W, Hellwig-Bürgel T (2002) Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-κB. FASEB J 16(13):1811–1813
Lennon GM, Ryan PC, Fitzpatrick JM (1993) Recovery of ureteric motility following complete and partial ureteric obstruction. BJU Int 72(5):702–707
Miyajima A, Chen J, Lawrence C, Ledbetter S, Soslow RA, Stern J et al (2000) Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 58(6):2301–2313
Nagib EM, El-Sayed MH, Ahmed MA, Youssef MH (2012) Intestinal motility in acute uremia and effects of erythropoietin. Saudi Med J 33(5):500–507
Nakatani T, Tamada S, Asai T, Iwai Y, Kim T, Tsujino T et al (2002) Role of renin-angiotensin system and nuclear factor-κB in the obstructed kidney of rats with unilateral ureteral obstruction. Jpn J Pharmacol 90(4):361–364
Ozdamar A, Topcu K, Gumustekin M, Gurel D, Gelal A, Ozer E et al (2006) Erythropoietin restores bowel damage and hypoperistalsis in gastroschisis. J Pediatr Surg 41(2):352–357
Power RE, Doyle BT, Higgins D, Brady HR, Fitzpatrick JM, Watson RWG (2004) Mechanical deformation induced apoptosis in human proximal renal tubular epithelial cells is caspase dependent. J Urol 171(1):457–461
Ryan PC, Lennon GM, McLean PA, Fitzpatrick JM (1994) The effects of acute and chronic JJ stent placement on upper urinary tract motility and calculus transit. Br J Urol 74(4):434–439
Srisawat N, Manotham K, Eiam-Ong S, Katavetin P, Praditpornsilpa K, Eiam-Ong S (2008) Erythropoietin and its non-erythropoietic derivative: do they ameliorate renal tubulointerstitial injury in ureteral obstruction? Int J Urol 15(11):1011–1017
Tashiro K, Tamada S, Kuwabara N, Komiya T, Takekida K, Asai T et al (2003) Attenuation of renal fibrosis by proteasome inhibition in rat obstructive nephropathy: possible role of nuclear factor κB. Int J Mol Med 12(4):587–592
Yang CW, Li C, Jung JY, Shin SJ, Choi BS, Lim SW et al (2003) Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. FASEB J 17(12):1754–1755
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Park, E., Cox, M., Scotland, K. et al. Erythropoietin promotes functional recovery via anti-apoptotic mechanisms in mouse unilateral ureteral obstruction. Cell Stress and Chaperones 25, 245–251 (2020). https://doi.org/10.1007/s12192-020-01067-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12192-020-01067-3