Control of the Epidermal Growth Factor Receptor and Its Ligands during Renal Injury

Aim: We studied control of the epidermal growth factor (EGF) receptor and its ligands during kidney injury, since they may be importantly involved in repair. Methods: The folic acid model of renal injury was used in these studies. Messenger RNA (mRNA) was evaluated by solution hybridization. Immunohistochemistry of transforming growth factor alpha (TGF-α) was also performed. Results: Twenty-four hours after folic acid induced acute renal injury, creatinine increased from 0.3 ± 0.03 mg/dl in controls to 2.0 ± 0.8 mg/dl in folic acid injured kidneys (n = 4, p < 0.03). mRNA for the EGF receptor was increased nearly sevenfold by 24 h, and mRNA for the receptor was increased as early as 1 h following folic acid treatment. EGF receptor ligand caused a profound downregulation of the receptors in proximal tubule basolateral membranes, but receptors returned rapidly to the membrane surface in injured kidneys. The mRNA levels for heparin-binding EGF and TGF-α, two EGF receptor ligands, increased within 1 h of injury. TGF-α mRNA increased from 1.0 ± 0.09 (relative densitometry units) in control animals to 2.9 ± 0.13 in folic acid treated rats at 24 h (n = 4, p < 0.01), and immunohistochemical staining for TGF-α increased in injured kidneys at distal nephron sites. Conclusions: These studies indicate that upregulation of the EGF receptor is related to an increase in mRNA. The rapid return of receptors to the membrane surface following ligand stimulation may be useful in maintaining a mitogenic stimulus. Multiple EGF-like ligands may be important in activating the upregulated EGF receptor during repair from renal injury.