Laminin 5 regulates polycystic kidney cell proliferation and cyst formation.
Renal cyst formation is the hallmark of autosomal dominant polycystic kidney disease (ADPKD). ADPKD cyst-lining cells have an increased proliferation rate and are surrounded by an abnormal extracellular matrix (ECM). We have previously shown that Laminin 5 (Ln-5, a alpha(3)beta(3)gamma(2) trimer) is aberrantly expressed in the pericystic ECM of ADPKD kidneys. We report that ADPKD cells in primary cultures produce and secrete Ln-5 that is incorporated to the pericystic ECM in an in vitro model of cystogenesis. In monolayers, purified Ln-5 induces ERK activation and proliferation of ADPKD cells, whereas upon epidermal growth factor stimulation blocking endogenously produced Ln-5 with anti-gamma(2) chain antibody reduces the sustained ERK activation and inhibits proliferation. In three-dimensional gel culture, addition of purified Ln-5 stimulates cell proliferation and cyst formation, whereas blocking endogenous Ln-5 strongly inhibits cyst formation. Ligation of alpha(6)beta(4) integrin, a major Ln-5 receptor aberrantly expressed by ADPKD cells, induces beta(4) integrin phosphorylation, ERK activation, cell proliferation, and cyst formation. These findings indicate that Ln-5 is an important regulator of ADPKD cell proliferation and cystogenesis and suggest that Ln-5 gamma(2) chain and Ln-5-alpha(6)beta(4) integrin interaction both contribute to these phenotypic changes.
Joly
Dominique
D
Université Paris-Descartes, FacultédeMédecine, Inserm U813, AP-HP, Hôpital Necker-Enfants-Malades, Service Néphrologie, 149 Rue de Sévres, 75015 Paris, France.
Berissi
Sophie
S
Bertrand
Amélie
A
Strehl
Laetitia
L
Patey
Natacha
N
Knebelmann
Bertrand
B
D002460:Cell Line; D049109:Cell Proliferation; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry / Q000502:physiology*; D008858:Microscopy, Phase-Contrast; D010766:Phosphorylation; D007690:Polycystic Kidney Diseases / Q000378:metabolism*; D011485:Protein Binding
D039161:Integrin alpha6beta4; D007797:Laminin; C095567:laminin alpha 3; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases