Heparin binding epidermal growth factor in renal ischaemia/reperfusion injury.
The epidermal growth factor (EGF) receptor and its ligands are crucially involved in the renal response to ischaemia. We studied the heparin binding-epidermal growth factor (HB-EGF), a major ligand for the EGF receptor, in experimental and human ischaemia/reperfusion injury (IRI). HB-EGF mRNA and protein expression was studied in rat kidneys and cultured human tubular (HK-2) cells that were subjected to IRI and in human donor kidneys during transplantation. The effect of EGF receptor inhibition was investigated in vivo and in vitro. Furthermore, urinary HB-EGF protein excretion was studied after renal transplantation. Finally, HB-EGF KO and WT mice were subjected to IRI to study the role of HB-EGF in renal injury. HB-EGF mRNA was significantly up-regulated in the early phase of IRI in rats, cells, and human donor biopsies. Treatment with PKI-166 reduces macrophage accumulation and interstitial alpha-SMA in the early phase of IRI in rats. In vitro, PKI-166 causes a marked reduction in HB-EGF-induced cellular proliferation. Urinary HB-EGF is increased after transplantation compared with control urines from healthy subjects. HB-EGF KO mice subjected to IRI revealed significantly less morphological damage after IRI, compared with WT mice. We conclude that IRI results in early induction of HB-EGF mRNA and protein in vivo and in vitro. Absence of HB-EGF and inhibition of the EGF receptor in the early phase of IRI has protective effects, suggesting a modulating role for HB-EGF.
Department of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands. g.m.mulder@path.umcg.nl
Gemma M
GM
Mulder
Willemijn N
WN
Nijboer
Marc A
MA
Seelen
Maria
M
Sandovici
Eelke M
EM
Bos
Wynand B W H
WB
Melenhorst
Monika
M
Trzpis
Niels J
NJ
Kloosterhuis
Lydia
L
Visser
Rob H
RH
Henning
Henri G D
HG
Leuvenink
Rutger J
RJ
Ploeg
Susan W
SW
Sunnarborg
Harry
H
van Goor
D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D008875:Middle Aged; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; C410026:PKI 166