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Control of the epidermal growth factor receptor and its ligands during renal injury
M K Hise1, M Salmanullah, L Liu
1Division of Nephrology, Department of Internal Medicine, University of Maryland Medical School, Baltimore, MD 21201, USA. mhise@medicine.umaryland.edu
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-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.
Insights
Epidermal Growth Factor (EGF) receptor and its ligands are upregulated during kidney injury, suggesting a role in renal repair. Rapid receptor return after stimulation may support healing.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Signaling
Background:
- Epidermal Growth Factor (EGF) receptor and its ligands are implicated in cellular repair processes.
- Understanding their role in kidney injury is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the control of the EGF receptor and its ligands during acute kidney injury.
- To determine the involvement of these factors in the renal repair process.
Main Methods:
- Utilized the folic acid model to induce acute renal injury in rats.
- Assessed messenger RNA (mRNA) levels of the EGF receptor and its ligands using solution hybridization.
- Performed immunohistochemistry to evaluate transforming growth factor alpha (TGF-alpha) expression.
Main Results:
- Folic acid induced significant kidney injury, evidenced by increased creatinine levels.
- EGF receptor mRNA showed a nearly sevenfold increase by 24 hours post-injury, with early detection at 1 hour.
- Levels of EGF receptor ligands, including heparin-binding EGF and TGF-alpha, increased within 1 hour of injury, with TGF-alpha showing a significant rise in mRNA and protein expression in injured kidney tissues.
Conclusions:
- Upregulation of the EGF receptor in kidney injury is directly correlated with increased mRNA levels.
- Rapid restoration of EGF receptors to the membrane surface after ligand stimulation may facilitate a sustained mitogenic signal.
- Multiple EGF-like ligands likely play a critical role in activating the upregulated EGF receptor during renal repair following injury.