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 i ts ligands during kidney injury, since they may be importantly involved in repair. Methods: The folic acid model of renal injury was used in these stu dies. Messenger RNA (mRNA) was evaluated by solution hybridization. Immunoh istochemistry of transforming growth factor alpha (TGF-alpha) was also perf ormed. Results: Twenty-four hours after folic acid induced acute renal inju ry, 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 re ceptor was increased nearly sevenfold by 24 h, and mRNA for the receptor wa s increased as early as 1 h following folic acid treatment. EGF receptor li gand caused a profound downregulation of the receptors in proximal tubule b asolateral membranes, but receptors returned rapidly to the membrane surfac e in injured kidneys. The mRNA levels for heparin-binding EGF and TGF-<alph a>, two EGF receptor ligands, increased within 1 h of injury. TGF-alpha mRN A increased from 1.0 +/- 0.09 (relative densitometry units) in control anim als to 2.9 +/- 0.13 in folic acid treated rats at 24 h (n = 4, p < 0.01), a nd immunohistochemical staining for TGF-<alpha> increased in injured kidney s at distal nephron sites. Conclusions: These studies indicate that upregul ation of the EGF receptor is related to an increase in mRNA. The rapid retu rn 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. Copyright (C) 2001 S. Karger AG, Basel.