Faculty Collaboration Database

EGF-related growth factors in the pathogenesis of murine ARPKD. Kidney Int 2004 Jun;65(6):2018-29

Date

05/20/2004

Pubmed ID

15149315

DOI

10.1111/j.1523-1755.2004.00623.x

Scopus ID

2-s2.0-2442683969 (requires institutional sign-in at Scopus site)   50 Citations

Abstract

BACKGROUND: Epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and their receptor, EGFR, play key roles in polycystic kidney disease (PKD) pathogenesis. Renal expression of two related growth factors, amphiregulin and heparin-binding EGF, has not been examined previously in PKD. The aims of this study of murine autosomal-recessive polycystic kidney disease (ARPKD) were (1) to characterize amphiregulin and heparin-binding EGF expression in cystic versus normal kidneys and cells; and (2) to identify the functional effects of abnormal EGF-related growth factor expression.

METHODS: Amphiregulin and heparin-binding-EGF expression were examined by immunohistology and Western blot of kidneys and conditionally-immortalized collecting tubule cells obtained from cystic bpk mice (a murine model of ARPKD) and normal littermates. EGF, TGF-alpha, amphiregulin, and heparin-binding EGF in vitro effects on cystic and control collecting tubule cells were assessed by cell proliferation, cyst fluid mitogenicity, and EGFR activation.

RESULTS: By immunohistology, amphiregulin and heparin-binding EGF localized to apical and basolateral surfaces of proximal tubule cysts > normal proximal tubules. In cystic collecting tubules, heparin-binding EGF (but not amphiregulin) localized to both apical and basolateral surfaces; whereas in normal collecting tubules, amphiregulin and heparin-binding EGF localized to the basolateral surface only. Increased amphiregulin and heparin-binding EGF expression by Western blot was seen in cystic vs. normal kidneys and increased heparin-binding EGF (but not amphiregulin) expression was present in cystic collecting tubule cell lines vs. controls. EGF, TGF-alpha, amphiregulin, and heparin-binding EGF were all mitogenic to cystic > control collecting tubule cells. Immunoprecipitation of EGF and TGF-alpha reduced cyst fluid mitogenicity by almost 80%, whereas heparin-binding EGF and amphiregulin immunoprecipitations had minimal effects. Differential receptor activation was also seen: Heparin-binding EGF markedly activated EGFR (>EGF = TGF-alpha > amphiregulin), with a greater effect seen in cystic vs. control collecting tubule cells.

CONCLUSION: Multiple EGF-related growth factors are abnormally expressed in murine ARPKD and may have differential roles in disease pathogenesis. In particular, newly identified abnormalities in heparin-binding EGF expression in cystic kidneys and cells may have important implications for disease pathogenesis.

Author List

MacRae Dell K, Nemo R, Sweeney WE Jr, Avner ED

Author

Ellis D. Avner MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amphiregulin
Animals
Cell Division
Cyst Fluid
Disease Models, Animal
EGF Family of Proteins
Epidermal Growth Factor
ErbB Receptors
Glycoproteins
Heparin-binding EGF-like Growth Factor
Intercellular Signaling Peptides and Proteins
Kidney Tubules, Collecting
Mice
Mice, Inbred BALB C
Mice, Mutant Strains
Mitogens
Polycystic Kidney, Autosomal Recessive
Transforming Growth Factor alpha