Effects of histamine and the h2 receptor antagonist ranitidine on ischemia-induced acute renal failure: involvement of IL-6 and vascular endothelial growth factor.
BACKGROUND
Vascular endothelial growth factor (VEGF) exerts cytoprotective, antiapoptotic and proangiogenic effects; its synthesis is induced by hypoxia, several cytokines and histamine. The effects of histamine and the H2 receptor antagonist ranitidine on renal VEGF and IL-6 synthesis were investigated in a well-established rat model of renal ischemia/reperfusion injury.


METHODS
Following 7 days of pretreatment with histamine (H group; n = 12), ranitidine (R group; n = 10) or vehicle (controls; n = 13), the left vascular pedicle was clamped for 50 min in uninephrectomized male rats and survival assessed in the different treatment groups. Additionally, renal IL-6 mRNA expression, as well as VEGF mRNA and protein abundance were measured in the three treatment groups following pretreatment only, 2 and 16 h after 50 min of renal ischemia (n = 6/group/timepoint).


RESULTS
Ranitidine significantly increased, while histamine significantly decreased survival following renal ischemia. Renal IL-6 mRNA expression increased 2 h after reperfusion in all groups and decreased thereafter, with the lowest level observed in the R group. While VEGF mRNA did not change in controls, histamine increased, whereas ranitidine decreased its expression during the follow-up. Two hours after ischemia a twofold increase in renal VEGF protein abundance was observed in controls and the H group and significantly higher values were noted in the R group at this time point. A further increase in VEGF protein was only present in the H group 16 h after reperfusion.


CONCLUSIONS
These results indicate an important role of histamine in kidney damage following renal ischemia. The beneficial effects of ranitidine were partly mediated by decreased IL-6 and VEGF mRNA expression and significant early increase in renal VEGF abundance.
Vannay
Adám
A
First Department of Pediatrics and Research Laboratory of the Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
Fekete
Andrea
A
Müller
Veronika
V
Strehlau
Jürgen
J
Viklicky
Ondrej
O
Veres
Tibor
T
Reusz
György
G
Tulassay
Tivadar
T
Szabó
Attila J
AJ
D058186:Acute Kidney Injury / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D006632:Histamine / Q000378:metabolism*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011899:Ranitidine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000473:pathology; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D006635:Histamine H2 Antagonists; D015850:Interleukin-6; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D006632:Histamine; D011899:Ranitidine