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      Cyclosporine or FK506 Decrease Mature Epidermal Growth Factor Protein Expression and Renal Tubular Regeneration in Rat Kidneys with Ischemia/Reperfusion Injury


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          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.

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          Most cited references3

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          Growth factors and apoptosis in acute renal injury.

          The precisely orchestrated pattern of growth factor expression within the kidney following acute renal injury indicates that growth factors regulate the process of repair. The use of growth factors as therapeutic agents to accelerate renal regeneration in this setting stems from this observation. In animal models of acute renal injury, administration of epidermal growth factor (EGF), insulin-like growth factor I (IGF-I) or hepatocyte growth factor (HGF) accelerates restoration of kidney function and normalization of histology post-acute renal injury and reduces mortality. IGF-I has been safely administered to humans and protects against post-surgical renal dysfunction. Renal cellular apoptosis occurs in a predictable pattern during recovery from acute ischemic injury. Renal apoptosis is regulated by agents both intrinsic and extrinsic to the kidney cell. The protooncogene, B-cell lymphoma/leukemia gene product-2 (bcl-2), is an important intrinsic factor. The growth factor, EGF, is an important extrinsic regulator. A thorough understanding of the control of renal apoptosis during recovery from ischemic injury coupled with an increased understanding of the roles that growth factors play in this process, is likely to result in the development of new therapies to enhance kidney regeneration.
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            Preconditioning with Sodium Arsenite Inhibits Apoptotic Cell Death in Rat Kidney with Ischemia/Reperfusion or Cyclosporine-Induced Injuries

            This study was performed to evaluate the effect of heat-shock protein (HSP)70 induction with sodium arsenite (SA) on ischemia/reperfusion (I/R) or cyclosporin A (CsA)-induced injuries in rat kidney. Rats were classified into five groups (sham, I/R, SA+I/R, I/R+CsA and SA+I/R+CsA groups) according to both the status of SA pretreatment and treatment with CsA. SA (6 mg/kg, i.v.) pretreatment was accomplished 12 h before I/R injury, and CsA (20 mg/kg, s.c.) was given subsequent to I/R injury. The effect of SA pretreatment on I/R injury was evaluated using measurements of renal function, the histopathology score, and assays for apoptosis (DNA fragmentation analysis, TUNEL staining, mRNA expressions of the pro-apoptotic genes and caspase activities). In addition, mitochondrial morphology was examined by electron microscopy. Induction of HSP70 with SA improved both renal function and the histopathology score as compared to the group without HSP70 induction. The assays for apoptosis revealed that SA pretreatment decreased the DNA laddering pattern, TUNEL-positive cells, mRNAs expression of pro-apoptotic genes and caspase activities as compared with the group without SA pretreatment. In addition, the mitochondrial morphology was well preserved in the groups with SA pretreatment. In conclusion, SA pretreatment prevents subsequent I/R or CsA-induced injuries in the rat kidney, and this renoprotective effect appears to be mediated by induction of HSP70.
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              Activation of Epidermal Growth Factor Receptor in the Early Phase after Renal Ischemia-Reperfusion in Rat

              In order to estimate a regenerative response in the early phase after renal ischemia-reperfusion in rat, we examined the time course of the activation of epidermal growth factor receptor (EGFR) as a response of signal transduction pathway after 45 min ischemia in kidney. The activation of EGFR was observed 5–30 min after the start of reperfusion. Simultaneously, superoxide anion/hydrogen peroxide generated in the mitochondrial fraction was elevated during the same period. On the other hand, the level of EGF decreased in a time-dependent manner. These results suggested that superoxide anion/hydrogen peroxide generated during the ischemia-reperfusion other than EGF could act as an activator for the EGFR. In summary, the activation of EGFR is important as a regenerative response at an early stage after the start of reperfusion in ischemic kidney.

                Author and article information

                S. Karger AG
                October 2002
                18 October 2002
                : 92
                : 4
                : 914-921
                Departments of Internal Medicine and Anatomy, College of Medicine, The Catholic University of Korea, Seoul, Korea
                65435 Nephron 2002;92:914–921
                © 2002 S. Karger AG, Basel

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                : 12 June 2002
                Page count
                Figures: 8, References: 35, Pages: 8
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/65435
                Self URI (text/html): https://www.karger.com/Article/FullText/65435
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                Ischemia-reperfusion injury,FK506,Cyclosporine,Epidermal growth factor


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