Control of the epidermal growth factor receptor and its ligands during renal injury.
OBJECTIVE
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-alpha) 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-alpha, two EGF receptor ligands, increased within 1 h of injury. TGF-alpha 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-alpha 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.
Hise
M K
MK
Division of Nephrology, Department of Internal Medicine, University of Maryland Medical School, Baltimore, MD 21201, USA. mhise@medicine.umaryland.edu
Salmanullah
M
M
Liu
L
L
Drachenberg
C I
CI
Papadimitriou
J C
JC
Rohan
R M
RM
D000208:Acute Disease; D000818:Animals; D003404:Creatinine / Q000097:blood; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005492:Folic Acid / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007511:Ischemia / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism*; D008024:Ligands; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D005492:Folic Acid; D003404:Creatinine; D066246:ErbB Receptors