Epidermal growth factor receptor regulation in rat kidney: two models of renal growth

Abstract

The binding of 125I-labeled epidermal growth factor (EGF) to plasma membranes prepared from rat kidney cortex was studied following unilateral nephrectomy, a model of proximal tubule cell hypertrophy, and following the administration of folic acid, a model of proximal tubule cell hyperplasia. Binding of 125I-EGF was a linear function of basolateral membrane protein content and time of incubation. Specific binding to luminal brush-border membranes was not evident in these studies. Neither insulin nor insulin-like growth factor I could displace EGF binding, indicating that binding was specific. Scatchard analysis revealed a single binding site. The KD in sham-operated animals 48 h after surgery was 11.2 +/- 1.4 nM, whereas Bmax averaged 95.2 +/- 4.1 fmol/mg protein (n = 3). Similar values were obtained in nephrectomized animals. The Bmax of folic acid-untreated animals averaged 212.5 +/- 6.9 fmol/mg 48 h after administration, whereas that of vehicle-injected controls averaged 85.4 +/- 9.2 (n = 3, P less than 0.001). Differences in binding were not related to changes in affinity, ligand degradation by the preparations, or receptor binding of endogenous EGF. These data indicate that regeneration following folic acid administration is associated with an upregulation of proximal nephron EGF receptors that may play an important role in the mitogenic response.

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

“…This increased EGF binding is detectable in the post-ischemic kidney by 24 h of reperfusion, whereas no changes are noted in the contralateral, non-ischemic kidney (6,7). Similar increases in '25I-EGF binding have been observed in rat kidney subjected to folic acid-induced injury (8). EGF production in the mammalian kidney has been localized to the thick ascending limb of Henle and distal convoluted tubule (9).…”

Importance of Functional EGF Receptors in Recovery from Acute Nephrotoxic Injury

“…EGF receptors are widely distributed in the kidney, both in the glomerulus and along the basolateral membranes of the tubular epithelium (26,27). After acute tubular injury, 125 I-EGF binding and EGF receptor mRNA expression increase (28,29), and there is evidence for EGFR activation after ischemia/reperfusion injury to the kidney (7,8). After either ischemic renal injury or nephrotoxic tubular injury in the rat, subcutaneous injection of EGF or TGF-␣ significantly accelerates [ 3 H]thymidine incorporation and recovery of tubular function (9 -11,30).…”

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.

“…EGF production in the normal adult mammalian kidney has been localized to the thick ascending limb/distal convoluted tubule (15). After ischemia, cis -platinum, or aminoglycoside-induced injury or acute ureteral obstruction, both preproEGF mRNA levels and urinary EGF excretion decrease and remain significantly depressed for up to 7 d (16, 17), whereas EGF receptor (EGF-R) binding increases (16,18).…”

“…I-EGF binding activity increases within 24 h of reperfusion in postischemic kidney (16,18), suggesting an important role of EGF-like growth factors in renal regeneration. However, preproEGF mRNA expression and urinary EGF excretion decrease for up to 7 d after injury (16,17).…”