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Cyclosporine or FK506 decrease mature epidermal growth factor protein expression and renal tubular regeneration in
Chul Woo Yang1, Seung Hun Lee, Sun Woo Lim
1Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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.
Insights
Cyclosporine A (CsA) or FK506 treatment delays kidney recovery after ischemia/reperfusion (I/R) injury by reducing epidermal growth factor (EGF) expression and tubular regeneration. This highlights a potential mechanism for impaired healing in I/R injury.
Area of Science:
- Nephrology
- Regenerative Medicine
- Immunopharmacology
Background:
- Epidermal growth factor (EGF) is crucial for kidney tubular regeneration following ischemia/reperfusion (I/R) injury.
- The impact of immunosuppressants like cyclosporine A (CsA) and FK506 on EGF expression and kidney repair remains unclear.
Purpose of the Study:
- To investigate the effect of CsA and FK506 on mature EGF expression in rat kidneys subjected to I/R injury.
- To evaluate the influence of CsA and FK506 on the process of tubular regeneration in I/R-injured kidneys.
Main Methods:
- Rat kidneys underwent I/R injury induced by renal artery clamping.
- EGF expression and tubular regeneration (BrdU-positive cells) were assessed at various time points post-injury.
- Dose-dependent effects of CsA and FK506 administered after reperfusion were analyzed.
Main Results:
- EGF expression peaked at day 1 post-I/R injury, with tubular regeneration maximal on days 2-3.
- Both CsA and FK506 treatment reduced EGF expression and the number of regenerating tubular cells.
- These inhibitory effects were dose-dependent for both CsA and FK506.
Conclusions:
- CsA and FK506 treatment appear to delay recovery from acute tubular necrosis in I/R-injured kidneys.
- The observed delay in recovery may be linked to the immunosuppressants' ability to decrease EGF expression.