Skip to main content
Erschienen in: Clinical and Experimental Nephrology 2/2018

01.04.2018 | Original article

Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model

verfasst von: Zhenyuan Li, Hao Yan, Jiangzi Yuan, Liou Cao, Aiwu Lin, Huili Dai, Zhaohui Ni, Jiaqi Qian, Wei Fang

Erschienen in: Clinical and Experimental Nephrology | Ausgabe 2/2018

Einloggen, um Zugang zu erhalten

Abstract

Background

Molecular mechanisms of peritoneal dialysis (PD) ultrafiltration failure, peritoneal neo-angiogenesis, and fibrosis remain to be determined. We aimed to determine the role of heparin-binding EGF-like growth factor (HB-EGF) inhibition on angiogenesis of peritoneal membrane in a PD rat model.

Methods

32 male Wistar rats were assigned into (1) control group; (2) uremic non-PD group: subtotal nephrectomy-induced uremic rats without PD; (3) uremic rats subjected to PD: uremic rats that were dialyzed with Dianeal® for 4 weeks; (4) CRM 197 group: dialyzed uremic rats were supplemented with CRM197, a specific HB-EGF inhibitor. Peritoneal transport function was examined by peritoneal equilibration test. Expression of HB-EGF and EGFR in peritoneal samples were examined by real-time PCR, immunohistochemical staining, and western blot.

Results

Progressive angiogenesis and fibrosis were observed in uremic PD rats, and there were associated with decreased net ultrafiltration (nUF), increased permeability of peritoneal membrane, and reduced expression of HB-EGF and EGFR protein and mRNA in uremic PD rats compared to uremic non-PD or control groups (both p < 0.05). CRM197 significantly induced peritoneal membrane permeability, decreased nUF, increased higher vessel density, and reduced pericyte count compared to that of uremic PD rats. The levels of HB-EGF and EGFR expression negatively correlated with vessel density in peritoneal membrane (both p < 0.001).

Conclusion

PD therapy was associated with peritoneal angiogenesis, functional deterioration, and downregulation of HB-EGF/EGFR. Pharmacological inhibition of HB-EGF promoted PD-induced peritoneal angiogenesis and fibrosis and ultrafiltration decline, suggesting that HB-EGF downregulation contributes to peritoneal functional deterioration in the uremic PD rat model.
Literatur
1.
Zurück zum Zitat De Vriese AS, Mortier S, Lameire NH. Neoangiogenesis in the peritoneal membrane: does it play a role in ultrafiltration failure? Nephrol Dial Transplant. 2001;16(11):2143–5.CrossRefPubMed De Vriese AS, Mortier S, Lameire NH. Neoangiogenesis in the peritoneal membrane: does it play a role in ultrafiltration failure? Nephrol Dial Transplant. 2001;16(11):2143–5.CrossRefPubMed
2.
Zurück zum Zitat Krediet RT, Lindholm B, Rippe B. Pathophysiology of peritoneal membrane failure. Perit Dial Int. 2000;20(Suppl 4):S22–42.PubMed Krediet RT, Lindholm B, Rippe B. Pathophysiology of peritoneal membrane failure. Perit Dial Int. 2000;20(Suppl 4):S22–42.PubMed
3.
Zurück zum Zitat Saxena R. Pathogenesis and treatment of peritoneal membrane failure. Pediatr Nephrol. 2008;23(5):695–703.CrossRefPubMed Saxena R. Pathogenesis and treatment of peritoneal membrane failure. Pediatr Nephrol. 2008;23(5):695–703.CrossRefPubMed
4.
Zurück zum Zitat Besner G, Higashiyama S, Klagsbrun M. Isolation and characterization of a macrophage-derived heparin-binding growth factor. Cell Regul. 1990;1(11):811–9.PubMedPubMedCentral Besner G, Higashiyama S, Klagsbrun M. Isolation and characterization of a macrophage-derived heparin-binding growth factor. Cell Regul. 1990;1(11):811–9.PubMedPubMedCentral
5.
Zurück zum Zitat Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991;251(4996):936–9.CrossRefPubMed Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991;251(4996):936–9.CrossRefPubMed
6.
Zurück zum Zitat Wolfson M, Piraino B, Hamburger RJ, Morton AR. A randomized controlled trial to evaluate the efficacy and safety of icodextrin in peritoneal dialysis. Am J Kidney Dis. 2002;40(5):1055–65.CrossRefPubMed Wolfson M, Piraino B, Hamburger RJ, Morton AR. A randomized controlled trial to evaluate the efficacy and safety of icodextrin in peritoneal dialysis. Am J Kidney Dis. 2002;40(5):1055–65.CrossRefPubMed
7.
Zurück zum Zitat Ongusaha PP, Kwak JC, Zwible AJ, Macip S, Higashiyama S, Taniguchi N, et al. HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer Res. 2004;64(15):5283–90.CrossRefPubMed Ongusaha PP, Kwak JC, Zwible AJ, Macip S, Higashiyama S, Taniguchi N, et al. HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer Res. 2004;64(15):5283–90.CrossRefPubMed
8.
Zurück zum Zitat Zhang L, Koivisto L, Heino J, Uitto VJ. Bacterial heat shock protein 60 may increase epithelial cell migration through activation of MAP kinases and inhibition of alpha6beta4 integrin expression. Biochem Biophys Res Commun. 2004;319(4):1088–95.CrossRefPubMed Zhang L, Koivisto L, Heino J, Uitto VJ. Bacterial heat shock protein 60 may increase epithelial cell migration through activation of MAP kinases and inhibition of alpha6beta4 integrin expression. Biochem Biophys Res Commun. 2004;319(4):1088–95.CrossRefPubMed
9.
Zurück zum Zitat Iivanainen E, Nelimarkka L, Elenius V, Heikkinen SM, Junttila TT, Sihombing L, et al. Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J. 2003;17(12):1609–21.CrossRefPubMed Iivanainen E, Nelimarkka L, Elenius V, Heikkinen SM, Junttila TT, Sihombing L, et al. Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J. 2003;17(12):1609–21.CrossRefPubMed
10.
Zurück zum Zitat Faull RJ, Stanley JM, Fraser S, Power DA, Leavesley DI. HB-EGF is produced in the peritoneal cavity and enhances mesothelial cell adhesion and migration. Kidney Int. 2001;59(2):614–24.CrossRefPubMed Faull RJ, Stanley JM, Fraser S, Power DA, Leavesley DI. HB-EGF is produced in the peritoneal cavity and enhances mesothelial cell adhesion and migration. Kidney Int. 2001;59(2):614–24.CrossRefPubMed
11.
Zurück zum Zitat Dateoka S, Ohnishi Y, Kakudo K. Effects of CRM197, a specific inhibitor of HB-EGF, in oral cancer. Med Mol Morphol. 2012;45(2):91–7.CrossRefPubMed Dateoka S, Ohnishi Y, Kakudo K. Effects of CRM197, a specific inhibitor of HB-EGF, in oral cancer. Med Mol Morphol. 2012;45(2):91–7.CrossRefPubMed
12.
Zurück zum Zitat Yagi H, Yotsumoto F, Sonoda K, Kuroki M, Mekada E, Miyamoto S. Synergistic anti-tumor effect of paclitaxel with CRM197, an inhibitor of HB-EGF, in ovarian cancer. Int J Cancer. 2009;124(6):1429–39.CrossRefPubMed Yagi H, Yotsumoto F, Sonoda K, Kuroki M, Mekada E, Miyamoto S. Synergistic anti-tumor effect of paclitaxel with CRM197, an inhibitor of HB-EGF, in ovarian cancer. Int J Cancer. 2009;124(6):1429–39.CrossRefPubMed
13.
Zurück zum Zitat Kunami N, Yotsumoto F, Ishitsuka K, Fukami T, Odawara T, Manabe S, et al. Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia. Anticancer Res. 2011;31(7):2483–8.PubMed Kunami N, Yotsumoto F, Ishitsuka K, Fukami T, Odawara T, Manabe S, et al. Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia. Anticancer Res. 2011;31(7):2483–8.PubMed
14.
Zurück zum Zitat Li AR, Chitale D, Riely GJ, Pao W, Miller VA, Zakowski MF, et al. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn. 2008;10(3):242–8.CrossRefPubMedPubMedCentral Li AR, Chitale D, Riely GJ, Pao W, Miller VA, Zakowski MF, et al. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn. 2008;10(3):242–8.CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Kakuta T, Tanaka R, Satoh Y, Izuhara Y, Inagi R, Nangaku M, et al. Pyridoxamine improves functional, structural, and biochemical alterations of peritoneal membranes in uremic peritoneal dialysis rats. Kidney Int. 2005;68(3):1326–36.CrossRefPubMed Kakuta T, Tanaka R, Satoh Y, Izuhara Y, Inagi R, Nangaku M, et al. Pyridoxamine improves functional, structural, and biochemical alterations of peritoneal membranes in uremic peritoneal dialysis rats. Kidney Int. 2005;68(3):1326–36.CrossRefPubMed
16.
Zurück zum Zitat Combet S, Miyata T, Moulin P, Pouthier D, Goffin E, Devuyst O. Vascular proliferation and enhanced expression of endothelial nitric oxide synthase in human peritoneum exposed to long-term peritoneal dialysis. J Am Soc Nephrol. 2000;11(4):717–28.PubMed Combet S, Miyata T, Moulin P, Pouthier D, Goffin E, Devuyst O. Vascular proliferation and enhanced expression of endothelial nitric oxide synthase in human peritoneum exposed to long-term peritoneal dialysis. J Am Soc Nephrol. 2000;11(4):717–28.PubMed
17.
Zurück zum Zitat Davies SJ, Phillips L, Griffiths AM, Russell LH, Naish PF, Russell GI. What really happens to people on long-term peritoneal dialysis? Kidney Int. 1998;54(6):2207–17.CrossRefPubMed Davies SJ, Phillips L, Griffiths AM, Russell LH, Naish PF, Russell GI. What really happens to people on long-term peritoneal dialysis? Kidney Int. 1998;54(6):2207–17.CrossRefPubMed
18.
Zurück zum Zitat Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR, et al. Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol. 2002;13(2):470–9.PubMed Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR, et al. Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol. 2002;13(2):470–9.PubMed
19.
Zurück zum Zitat Davies SJ, Bryan J, Phillips L, Russell GI. Longitudinal changes in peritoneal kinetics: the effects of peritoneal dialysis and peritonitis. Nephrol Dial Transplant. 1996;11(3):498–506.CrossRefPubMed Davies SJ, Bryan J, Phillips L, Russell GI. Longitudinal changes in peritoneal kinetics: the effects of peritoneal dialysis and peritonitis. Nephrol Dial Transplant. 1996;11(3):498–506.CrossRefPubMed
20.
Zurück zum Zitat Ho-dac-Pannekeet MM, Atasever B, Struijk DG, Krediet RT. Analysis of ultrafiltration failure in peritoneal dialysis patients by means of standard peritoneal permeability analysis. Perit Dial Int. 1997;17(2):144–50.PubMed Ho-dac-Pannekeet MM, Atasever B, Struijk DG, Krediet RT. Analysis of ultrafiltration failure in peritoneal dialysis patients by means of standard peritoneal permeability analysis. Perit Dial Int. 1997;17(2):144–50.PubMed
21.
Zurück zum Zitat Selgas R, Fernandez-Reyes MJ, Bosque E, Bajo MA, Borrego F, Jimenez C, et al. Functional longevity of the human peritoneum: how long is continuous peritoneal dialysis possible? Results of a prospective medium long-term study. Am J Kidney Dis. 1994;23(1):64–73.CrossRefPubMed Selgas R, Fernandez-Reyes MJ, Bosque E, Bajo MA, Borrego F, Jimenez C, et al. Functional longevity of the human peritoneum: how long is continuous peritoneal dialysis possible? Results of a prospective medium long-term study. Am J Kidney Dis. 1994;23(1):64–73.CrossRefPubMed
22.
Zurück zum Zitat Krediet RT. The peritoneal membrane in chronic peritoneal dialysis. Kidney Int. 1999;55(1):341–56.CrossRefPubMed Krediet RT. The peritoneal membrane in chronic peritoneal dialysis. Kidney Int. 1999;55(1):341–56.CrossRefPubMed
24.
Zurück zum Zitat Mehta VB, Besner GE. HB-EGF promotes angiogenesis in endothelial cells via PI3-kinase and MAPK signaling pathways. Growth Factors. 2007;25(4):253–63.CrossRefPubMed Mehta VB, Besner GE. HB-EGF promotes angiogenesis in endothelial cells via PI3-kinase and MAPK signaling pathways. Growth Factors. 2007;25(4):253–63.CrossRefPubMed
25.
Zurück zum Zitat Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21(2):193–215.CrossRefPubMed Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21(2):193–215.CrossRefPubMed
26.
Zurück zum Zitat Yung S, Chan TM. Mesothelial cells. Perit Dial Int. 2007;27(Suppl 2):S110–5.PubMed Yung S, Chan TM. Mesothelial cells. Perit Dial Int. 2007;27(Suppl 2):S110–5.PubMed
27.
Zurück zum Zitat Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97(6):512–23.CrossRefPubMed Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97(6):512–23.CrossRefPubMed
28.
Zurück zum Zitat Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci USA. 2003;100(6):3221–6.CrossRefPubMedPubMedCentral Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci USA. 2003;100(6):3221–6.CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood. 2010;116(22):4720–30.CrossRefPubMedPubMedCentral Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood. 2010;116(22):4720–30.CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Yu X, Radulescu A, Chen CL, James IO, Besner GE. Heparin-binding EGF-like growth factor protects pericytes from injury. J Surg Res. 2012;172(1):165–76.CrossRefPubMed Yu X, Radulescu A, Chen CL, James IO, Besner GE. Heparin-binding EGF-like growth factor protects pericytes from injury. J Surg Res. 2012;172(1):165–76.CrossRefPubMed
31.
Zurück zum Zitat Wang L, Liu N, Xiong C, Xu L, Shi Y, Qiu A, et al. Inhibition of EGF receptor blocks the development and progression of peritoneal fibrosis. J Am Soc Nephrol. 2016;27(9):2631–44.PubMed Wang L, Liu N, Xiong C, Xu L, Shi Y, Qiu A, et al. Inhibition of EGF receptor blocks the development and progression of peritoneal fibrosis. J Am Soc Nephrol. 2016;27(9):2631–44.PubMed
Metadaten
Titel
Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model
verfasst von
Zhenyuan Li
Hao Yan
Jiangzi Yuan
Liou Cao
Aiwu Lin
Huili Dai
Zhaohui Ni
Jiaqi Qian
Wei Fang
Publikationsdatum
01.04.2018
Verlag
Springer Singapore
Erschienen in
Clinical and Experimental Nephrology / Ausgabe 2/2018
Print ISSN: 1342-1751
Elektronische ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-017-1440-7

Weitere Artikel der Ausgabe 2/2018

Clinical and Experimental Nephrology 2/2018 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.