Cyclosporine or FK506 decrease mature epidermal growth factor protein expression and renal tubular regeneration in rat kidneys with ischemia/reperfusion injury.
BACKGROUND
Epidermal growth factor (EGF) plays an important role in tubular regeneration in kidneys with ischemia/reperfusion (I/R) injury. This study was undertaken to evaluate the influence of cyclosporine A (CsA) or FK506 on mature EGF expression and tubular regeneration in rat kidneys with I/R injury.


METHODS
Two separate studies were performed. First, the expression of EGF and tubular regeneration was observed in rat kidneys with I/R injury on days 1, 2, 3, 5, and 7. Second, the dose-dependent response of EGF expression and tubular regeneration to CsA (5, 10, and 20 mg/kg) or FK506 (0.25, 0.5, and 1.0 mg/kg) was observed in rat kidneys with I/R injury. I/R injury was induced by clamping both renal arteries for 45 min, and CsA or FK506 was injected just after release of vascular clamps. Rats were sacrificed on day 1 for evaluation of EGF expression, and on day 2 for evaluation of BudU-positive cells. Renal function, tubular injury score, EGF expression assessed by immunoblotting, levels of CsA and FK506 in whole blood, and immunostaining for BrdU was studied.


RESULTS
EGF expression was maximal on day 1 (cortex, 29-fold; medulla, 31-fold compared with sham-operated controls), and renal tubular regeneration measured with the number of BrdU-positive cells was maximal on days 2 and 3 in kidney with I/R injury, and thereafter the level of EGF and the number of BrdU-positive cells decreased progressively. CsA or FK506 treatment to ischemic rat kidneys reduced the expression of EGF and the number of BrdU-positive cells in a dose-dependent manner.


CONCLUSIONS
CsA or FK506 treatment delays recovery from acute tubular necrosis, and this may be associated with decreased EGF expression by CsA or FK506.
Yang
Chul Woo
CW
Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Lee
Seung Hun
SH
Lim
Sun Woo
SW
Jung
Ju Young
JY
Kim
Wan Young
WY
Kim
Hyung Wook
HW
Choi
Bum Soon
BS
Li
Can
C
Cha
Jung Ho
JH
Kim
Yong Soo
YS
Kim
Jin
J
Bang
Byung Kee
BK
D000818:Animals; D000963:Antimetabolites / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007684:Kidney Tubules / Q000033:anatomy & histology / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology*
D000963:Antimetabolites; D007166:Immunosuppressive Agents; D004815:Epidermal Growth Factor; D016572:Cyclosporine; D001973:Bromodeoxyuridine; D016559:Tacrolimus