Epidermal growth factor accelerates renal repair in mercuric chloride nephrotoxicity

Abstract

Repair and recovery of ischemic or nephrotoxic acute renal failure (ARF) are dependent upon renal tubule cell regeneration. Because epidermal growth factor (EGF) is a potent growth promoter to renal tubule cells, experiments were undertaken to assess the effects of exogenous administration of EGF during the recovery phase of HgCl2-induced ARF. Rats were administered HgCl2 (5 mg/kg sc), and [3H]thymidine incorporation into renal tissue and blood urea nitrogen (BUN) and serum creatinine concentrations were measured at various times after toxin administration. EGF (20 microgram) was administered subcutaneously 2 or 4 h after HgCl2 injection. Exogenous EGF resulted in greater levels of renal [3H]thymidine incorporation into renal proximal tubule cells compared with those observed in nontreated animals at several time points in the first 48 h after toxic injury. Morphometric analysis of histoautoradiograph sections of renal tissue demonstrated that greater than 96% of labeled cells were tubular in all examined sections. This EGF-related acceleration in DNA synthesis was associated with significantly lower peak BUN and serum creatinine levels, averaging 213 +/- 23 and 6.54 +/- 0.72 (SE) mg/dl, respectively, at 3 days in EGF-treated nephrotoxic rats compared with peak levels of 359 +/- 40 and 9.92 +/- 1.67 mg/dl (P less than 0.001, n = 7-16) at 5 days in non-EGF-treated nephrotoxic rats. EGF treatment also was associated with a return to near normal BUN and serum creatinine levels approximately 4 days earlier than that observed in non-EGF-treated animals. These findings demonstrate that exogenous EGF accelerates the repair process of the kidney after a severe toxic insult.

Induction of heparin-binding epidermal growth factor-like growth factor mRNA in rat kidney after acute injury.

“…In the post-ischemic kidney, a significant increase in HB-EGF mRNA levels was observed within 1 h of reperfusion. Expression of HB-EGF mRNA remained elevated at 6 h of reperfusion (8.0+2.0-fold of that in the contralateral kidney; n = 5; P < 0.05) and in some experiments was still elevated at 24 and 48 h. Acute injury and subsequent regeneration of tubular epithelial cells are also induced by a variety of nephrotoxins, including mercuric chloride (1,4). Mercuric chloride administration induced expression of HB-EGF mRNA in the kidney within 5 h (Fig.…”

“…Retrograde aortic perfusion with phosphate buffered saline was performed to remove blood from the kidney. In separate experiments, renal tubular injury was induced by a subcutaneous administration of mercuric chloride (5 mg/kg body wt) 5 h before time of killing (4).…”

“…In the rat, subcutaneous injection of EGF significantly accelerates both [3H]thymidine incorporation in tubular epithelial cells and recovery of tubular functions occurring in response to ischemia/reperfusion injury or nephrotoxic injury to the kidney (3)(4)(5). Continuous infusion of EGF by intra-aortic osmotic minipump has also been shown to augment recovery of tubular functions in the post-ischemic rat kidney (6).…”

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.…”

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

“…These growth factors include epidermal growth factor, hepatocyte growth factor (HGF), 1 and insulin-like growth factor-I (9-13). A number of studies have investigated the potential role of EGF and/or the EGF family of growth factors in renal injury (9)(10)(11)14). EGF production in the normal adult mammalian kidney has been localized to the thick ascending limb/distal convoluted tubule (15).…”