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

Abstract

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.

Upregulation of Rat Renal Cortical Organic Anion Transporter (OAT1 and OAT3) Expression in Response to Ischemia/Reperfusion Injury

“…It has recently been described that the epidermal growth factor upregulates OAT1 and OAT3. Interestingly, the expression of epidermal growth factor is increased in renal IRI in previous reports [44, 45]. All these findings taken together, the increased expression of OAT1 and OAT3 may be the result of compensations in the relative normal renal tubular cells when severe renal tissue damage occurs.…”

Calcineurin Inhibitor Effects on Growth and Phenotype of Human Airway Epithelial Cells In Vitro

“…Mucin production and homeostatic repair of epithelial cell injury in airway epithelial cells is linked to ion transport, nucleotide and epidermal growth factor receptor integrity (58)(59)(60). Yang and colleagues found cyclosporin decreased mature epidermal growth factor expression in a renal transplant ischemiareperfusion model (61), and therefore investigation of this ligand in well-differentiated cyclosporin-treated hTBEC cultures would be informative.…”

Preconditioning with 1,25-Dihydroxyvitamin D₃ Protects against Subsequent Ischemia-Reperfusion Injury in the Rat Kidney

“…Only tubules in the outer stripe of the outer medulla (most sensitive zone for ischemic injury), a minimum of 20 fields/section of tubular injury, were assessed using a color image analyzer (TDI Scope Eye version 3.0 for Windows; Olympus, Tokyo, Japan). Briefly, the image was captured, and the extent of the most sensitive zone for ischemic injury was quantified using the polygon program by counting the percentage of areas injured per field of medulla under ×100 magnification, as previously reported [12]. Histopathological analyses were performed in the randomly selected most sensitive zone for ischemic injury fields (outer stripe of the outer medulla) of sections by a pathologist blinded to the identity of the treatment groups.…”

“…The role of HSP70 in ameliorating I/R injury has been documented in transfected cells and transgenic murine tissues overexpressing HSP70 [5, 6]. In general, HSP70 is induced in response to a variety of stresses [7, 8], but nontoxic HSP70 inducers have also been reported [9, 10, 11, 12]. Therefore, it would be of great therapeutic benefit to identify compounds that are clinically safe, yet able to induce HSP70 in the kidney.…”