Epidermal growth factor accelerates functional recovery from ischaemic acute tubular necrosis in the rat: Role of the epidermal growth factor receptor

Abstract

1. Severe, ischaemic, acute tubular necrosis was induced in rats by bilateral occlusion of the renal arteries. The experimental group received exogenous epidermal growth factor infused directly into the renal arterial circulation. Serum creatinine concentration was measured daily for 1 week. Epidermal growth factor receptor binding was measured by autoradiography of whole kidney sections. Renal cell proliferation was measured by incorporation of [3H]thymidine into DNA. 2. Serum creatinine concentration increased after acute tubular necrosis with a peak at 48 h and remained elevated above control levels after 7 days. Binding of radiolabelled epidermal growth factor occurred in all regions of the kidney 48 h after ischaemia. Treatment with exogenous epidermal growth factor attenuated the rise in serum creatinine by 4 days after acute tubular necrosis and after 7 days serum creatinine was lower than in animals that did not receive epidermal growth factor. Infusion of epidermal growth factor also increased renal DNA synthesis. 3. The increase in epidermal growth factor binding in the kidney after acute tubular necrosis and the attenuation of the increase in serum creatinine concentration by administration of exogenous epidermal growth factor, suggest a role for epidermal growth factor in recovery from ischaemic damage. The increase in DNA synthesis in response to epidermal growth factor indicates that its effect may be due, at least in part, to accelerated tubular cell proliferation.

Insulin-like growth factor I gene expression in isolated rat renal collecting duct is stimulated by epidermal growth factor.

“…They suggest that these changes could be a consequence of kidney damage and may reflect the events leading to renal failure or alternatively, and that reduced EGF synthesis is an adaptation permitting restoration ofkidney function (26). Support for the former hypothesis is provided by Humes et al (27) and Norman et al (28) who showed that administration of EGF to rats enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure. In view of the action of EGF to enhance IGF I gene expression in collecting duct, it is possible that production of endogenous EGF provides a stimulus for IGF I expression during ischemic renal injury.…”

Adenine nucleotides stimulate migration in wounded cultures of kidney epithelial cells.

“…Infusion ofadenine nucleotides or EGF can speed recovery of injured kidney tubules in rats with experimental acute renal failure (7,(54)(55)(56). The results indicated that EGF was as potent as adenosine and adenine nucleotides, basic FGF and IGF-I were much less stimulatory, and PDGF, IGF-II, and acidic FGF had no effect.…”

Increased epidermal growth factor in experimental diabetes related kidney growth in rats

“…For instance, the renal growth that follows unilateral nephrectomy is associated with increased renal EGF [11,10] and the associated tubular cell hyperplasia can be reduced by the administration of anti-EGF antibodies [28]. In acute tubular necrosis following ischaemic injury [29,30] or mercuric chloride toxicity exogenously administered EGF accelerates tubular regeneration and recovery. The factors responsible for increased EGF during early diabetes remain speculative.…”