Dexamethasone ameliorates renal ischemia-reperfusion injury.
In the setting of renal ischemia-reperfusion injury (IRI), the effect and mechanism of action of glucocorticoids are not well understood. In rat renal IRI, a single dose of dexamethasone administered before ischemia, or at the onset of reperfusion, ameliorated biochemical and histologic acute kidney injury after 24 h. Dexamethasone upregulated Bcl-xL, downregulated ischemia-induced Bax, inhibited caspase-9 and caspase-3 activation, and reduced apoptosis and necrosis of proximal tubular cells. In addition, dexamethasone decreased the number of infiltrating neutrophils and ICAM-1. We observed the protective effect of dexamethasone in neutrophil-depleted mice, suggesting a neutrophil-independent mechanism. In vitro, dexamethasone protected human kidney proximal tubular (HK-2) cells during serum starvation and IRI-induced apoptosis, but inhibition of MEK 1/2 abolished its anti-apoptotic effects in these conditions. Dexamethasone stimulated rapid and transient phosphorylation of ERK 1/2, which required the presence of the glucocorticoid receptor and was independent of transcriptional activity. In summary, in the setting of renal ischemia-reperfusion injury, dexamethasone directly protects against kidney injury by a receptor-dependent, nongenomic mechanism.
Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, St. Bartholomew's, University of London, London EC1M 6BQ, United Kingdom. drksanjeev@yahoo.com
Sanjeev
S
Kumar
David A
DA
Allen
Julius E
JE
Kieswich
Nimesh S A
NS
Patel
Steven
S
Harwood
Emanuela
E
Mazzon
Salvatore
S
Cuzzocrea
Martin J
MJ
Raftery
Christoph
C
Thiemermann
Muhammad M
MM
Yaqoob
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*
D005938:Glucocorticoids; D003907:Dexamethasone