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Volume 272, Number 49, Issue of December 5, 1997 pp. 31036-31042
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The Membrane-bound Form of Heparin-binding Epidermal Growth Factor-like Growth Factor Promotes Survival of Cultured Renal Epithelial Cells

(Received for publication, March 25, 1997, and in revised form, August 29, 1997)

From the Department of Medicine, Vanderbilt University School of Medicine and the Department of Veterans Affairs Medical Center, Nashville, Tennessee 37232

To understand whether expression of membrane-anchored heparin binding epidermal growth factor (proHB-EGF) is involved in renal epithelial cell survival, rat membrane-bound HB-EGF precursor was stably transfected into a renal epithelial cell line, NRK 52E cells (NRK^proHB-EGF). When exposed to 10% fetal calf serum (FCS), there were no differences in growth rates among wild-type (WT), vector-transfected (NRK^vector), and NRK^proHB-EGF. However, when cells were grown in the presence of 1% FCS, the growth rate of NRK^proHB-EGF was 65% faster. When confluent cell monolayers were exposed to H₂O₂ or etoposide, WT or NRK^vector exhibited significant apoptotic bodies and DNA laddering; in contrast, NRK^proHB-EGF were resistant to both stimuli, as indicated by increased cell viability and marked decrease of apoptotic bodies and DNA laddering. When plated at high density onto plastic dishes without FCS, WT and NRK^vector formed few attachments, did not proliferate, and underwent apoptosis. By day 3, no cells survived. Addition of exogenous recombinant HB-EGF (10⁸ M) to WT or NRK^vector increased cell survival by <10% and incubation with conditioned media of NRK^proHB-EGF had no effect. In contrast, NRK^proHB-EGF attached and formed epithelial colonies, although they did not proliferate. After 3 days, cell viability was 84% of the initial cell number plated, and no evidence of apoptosis was present. When plated in 10% FCS, NRK^proHB-EGF attachment to plastic substratum at 1, 2, and 3 h was 250% greater than that of WT or NRK^vector. Addition of exogenous recombinant human HB-EGF to WT or NRK^vector increased attachment by <50%. When grown on poly(2-hydroxyethyl methacrylate) or in the presence of the integrin receptor-blocking peptide GRGDTP, neither WT nor NRK^vector attached to the substratum or formed cell-cell attachments. Compared with WT or NRK^vector, NRK^proHB-EGF exhibited 300% greater cell viability on either poly(2-hydroxyethyl methacrylate)-coated dishes or in the presence of GRGDTP and formed cell clusters. When plated at low density (1 × 10³ cells/1.5-cm dish) or at high density in the presence of an anti-HB-EGF blocking antibody, NRK^proHB-EGF failed to form epithelial colonies. Addition of formalin fixed NRK^proHB-EGF promoted EGF receptor tyrosine phosphorylation in quiescent A431 cells and stimulated DNA synthesis and prevented H₂O₂-induced apoptosis in renal epithelial cells. These results indicate that membrane-bound HB-EGF promotes renal epithelial cell survival, possibly by promoting cell-matrix and cell-cell interactions. The failure of either conditioned media or exogenous HB-EGF to reproduce these findings suggests that juxtacrine or tightly coupled paracrine interactions underlie this cytoprotection.

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