Increased soluble EGF after ischemia is accompanied by a decrease in membrane-associated precursors

Schaudies, R. P.; Johnson, John P.

doi:10.1152/ajprenal.1993.264.3.f523

Cited by 17 publications

(20 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This antibody allowed us to demonstrate the presence of immunoreactive EGF in the exocrine rat lacrimal gland. In this tissue EGF was shown to be stored as its high molecular weight membrane-anchored precursor as already shown in kidney (12,36,37,39). Immunoreactive rat EGF is also present in corresponding secretory fluids, i.e.…”

Section: Discussionsupporting

confidence: 64%

“…In order to lead to the ultimate, mature 6-kDa form of the molecule, the ectodomain needs to be further maturated in the extracellular medium. It has already been shown that, in vitro, mature EGF could be released from its precursor through the action of different type of proteases; acidic protease such as pepsin (36) or serine-proteases such as trypsin (22,39,41) and plasmin (44). Moreover, membrane fractions of both kidney (45,46) and mammary gland (47) contain a membrane-bound proteolytic activity that colocalized with pro-EGF and released soluble EGF from its membraneassociated precursor.…”

Section: Epidermal Growth Factor (Egf)mentioning

confidence: 99%

See 1 more Smart Citation

Regulated Cell Surface Pro-EGF Ectodomain Shedding Is a Zinc Metalloprotease-dependent Process

Gall

Auger

Dreux

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Epidermal growth factor receptor (EGFR) ligands are synthesized as type I membrane protein precursors exposed at the cell surface. Shedding of the ectodomain of these proteins is the way cells regulate the equilibrium between cell-associated and diffusible forms of these growth factors. Whereas the regulated shedding of transforming growth factor-␣, HB-EGF, and amphiregulin precursors have been clearly established, regulation of full-length pro-EGF shedding has not been clearly demonstrated. Here, using both wild-type and M2 mutant CHO-K1 as well as HeLa cell lines transiently transfected with epitope-tagged rat pro-EGF expression plasmid, we demonstrate that these cells synthesize EGF as a high molecular weight membrane-associated precursor glycoprotein expressed at the cell surface. All cell lines are able to release the entire ectodomain of pro-EGF in the extracellular medium following juxtamembrane cleavage of the precursor once it is present at the cell surface. More significantly we clearly established that CHO-M2 and HeLa cells only constitutively release low levels of pro-EGF. This shedding is a regulated phenomenon in wild-type CHO cells where it can be induced by different agents such as phorbol 12-myristate 13-acetate (PMA), pervanadate, and serum but not by calcium ionophores. Using specific inhibitors as well as protein kinase C (PKC) depletion, PMA stimulation was shown to be completely dependent on PKC activation whereas pervanadate and serum stimulation were not. Regulated ectodomain shedding involves the activity of a zinc metalloprotease as determined by inhibition with phenantrolin and TAPI-2 and by the results obtained with the CHO-M2 shedding defective mutant cell line. Comparison of the ability of CHO and HeLa cell lines to shed pro-EGF and pro-TNF-␣ upon stimulation greatly suggests that TACE (ADAM 17) may not be the ectoprotease involved in the secretion of pro-EGF ectodomain and that this protease, which remains to be identified, shows a restricted cellular expression pattern.

show abstract

Section: Discussionsupporting

confidence: 64%

Section: Epidermal Growth Factor (Egf)mentioning

confidence: 99%

Regulated Cell Surface Pro-EGF Ectodomain Shedding Is a Zinc Metalloprotease-dependent Process

Gall

Auger

Dreux

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…EGF production in the adult mouse kidney has been localized to the thick ascending limb/ distal convoluted tubule (33). After either ischemic or nephrotoxic injury, both preproEGF mRNA levels and urinary EGF levels decrease and remain significantly depressed for up to 7 d (28,34), although it has been reported that there is increased processing of preproEGF to its soluble, active form in response to acute ischemic renal injury (35). In addition, HB-EGF expression has been shown to increase significantly in rat kidney in response to acute tubular injury induced by mercuric chloride, ischemia, aminoglycosides, or folic acid (4 -6).…”

Section: Discussionmentioning

confidence: 99%

Importance of Functional EGF Receptors in Recovery from Acute Nephrotoxic Injury

Wang

Chen

Wang

et al. 2003

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. Previous studies have demonstrated increased renal expression of EGF receptor (EGFR) and EGFR ligands in response to acute toxic or ischemic renal tubular injury and have indicated that exogenous administration of EGF accelerates recovery from such injury. However, no studies to date have proved definitively an essential role for EGFR-mediated responses in regeneration after tubule injury. To this end, waved-2 (wa-2) mice, which contain a point mutation in EGFR that reduces receptor tyrosine kinase activity by Ͼ90%, were studied. These mice have a mild phenotype (wavy coat, curly whiskers, and runted stature) and normally developed kidneys. Acute nephrotoxic injury was induced in wa-2 and wild-type mice with HgCl 2 . One day after HgCl 2 injection, functional renal compromise was comparable in wild-type and wa-2 mice. However, the rates of recovery of serum blood urea nitrogen and creatinine levels were markedly slower in wa-2 mice. Histologic evidence of tubular injury also was more severe and persisted longer in wa-2 mice. Furthermore, their kidneys demonstrated reduced levels of DNA synthesis and increased TdT-mediated dUTP nick-end labeling staining. These studies indicate that functional EGFR activity is an essential component of the kidney's ability to recover from acute injury and that EGFR may regulate genes involved in growth, repair, and cell survival in the kidney.

show abstract

“…In rat kidneys with I/R injury, EGF immunoreactivity detected by immunohistochemical study decreases [27, 28, 29]but concentration of mature EGF rose 7- to 10-fold [21]. At the mRNA level, the EGF precursor [30]and prepro EGF mRNA [31]are decreased during renal tubular regeneration. Thus, it is suggested that that mature EGF protein is present in renal tubular cells as preformed form, and released when kidney is damaged by I/R injury.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine or FK506 Decrease Mature Epidermal Growth Factor Protein Expression and Renal Tubular Regeneration in Rat Kidneys with Ischemia/Reperfusion Injury

Yang¹,

Lee²,

Lim³

et al. 2002

Nephron

View full text Add to dashboard Cite

Background: Epidermal growth factor (EGF) plays an important role in tubular regeneration in kidneys with ischemia/reperfusion (I/R) injury. This study was undertaken to evaluate the influence of cyclosporine A (CsA) or FK506 on mature EGF expression and tubular regeneration in rat kidneys with I/R injury. Methods: Two separate studies were performed. First, the expression of EGF and tubular regeneration was observed in rat kidneys with I/R injury on days 1, 2, 3, 5, and 7. Second, the dose-dependent response of EGF expression and tubular regeneration to CsA (5, 10, and 20 mg/kg) or FK506 (0.25, 0.5, and 1.0 mg/kg) was observed in rat kidneys with I/R injury. I/R injury was induced by clamping both renal arteries for 45 min, and CsA or FK506 was injected just after release of vascular clamps. Rats were sacrificed on day 1 for evaluation of EGF expression, and on day 2 for evaluation of BudU-positive cells. Renal function, tubular injury score, EGF expression assessed by immunoblotting, levels of CsA and FK506 in whole blood, and immunostaining for BrdU was studied. Results: EGF expression was maximal on day 1 (cortex, 29-fold; medulla, 31-fold compared with sham-operated controls), and renal tubular regeneration measured with the number of BrdU-positive cells was maximal on days 2 and 3 in kidney with I/R injury, and thereafter the level of EGF and the number of BrdU-positive cells decreased progressively. CsA or FK506 treatment to ischemic rat kidneys reduced the expression of EGF and the number of BrdU-positive cells in a dose-dependent manner. Conclusions: CsA or FK506 treatment delays recovery from acute tubular necrosis, and this may be associated with decreased EGF expression by CsA or FK506.

show abstract

Increased soluble EGF after ischemia is accompanied by a decrease in membrane-associated precursors

Cited by 17 publications

References 1 publication

Regulated Cell Surface Pro-EGF Ectodomain Shedding Is a Zinc Metalloprotease-dependent Process

Regulated Cell Surface Pro-EGF Ectodomain Shedding Is a Zinc Metalloprotease-dependent Process

Importance of Functional EGF Receptors in Recovery from Acute Nephrotoxic Injury

Cyclosporine or FK506 Decrease Mature Epidermal Growth Factor Protein Expression and Renal Tubular Regeneration in Rat Kidneys with Ischemia/Reperfusion Injury

Contact Info

Product

Resources

About