Heparin-binding epidermal growth factor and Src family kinases in proliferation of renal epithelial cells

Shougang Zhuang, Gilbert R. Kinsey, Kyle Rasbach, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Our recent studies have shown that proliferation of renal proximal tubular cells (RPTC) in the absence of growth factors requires activation of the epidermal growth factor (EGF) receptor. We sought to identify the endogenous EGF receptor ligand and investigate the mechanism(s) by which RPTC proliferate in different models. RPTC expressed both pro- and cleaved forms of heparin-binding epidermal growth factor (HB-EGF) and several metalloproteinases (MMP-2, -3, -9, and ADAM10, ADAM17) that have been reported to cleave HB-EGF. Treatment of RPTC with CRM 197, an inhibitor of HB-EGF binding to the EGF receptor, or downregulation of HB-EGF with small interfering RNA inhibited RPTC proliferation following plating. Furthermore, GM6001 (pan-MMP inhibitor), tumor-necrosis factor protease inhibitor-1 (TAPI-1; MMP and ADAM17 inhibitor), and GW280264X (ADAM10 and -17 inhibitor), but not GI254023X (ADAM10 inhibitor), attenuated the proliferation after plating. Although EGF receptor activation is required for RPTC proliferation after oxidant injury, CRM197, GM6001, and TAPI-1 did not block this response. In contrast, inhibition of Src with PP1 blocked EGF receptor activation and RPTC proliferation after oxidant injury. In addition, PP1 treatment attenuated HB-EGF-enhanced RPTC proliferation. We suggest that RPTC proliferation after plating is mediated by HB-EGF produced through an autocrine/paracrine mechanism and RPTC proliferation following oxidant injury is mediated by Src without involvement of HB-EGF.

Original languageEnglish (US)
Pages (from-to)F459-F468
JournalAmerican Journal of Physiology - Renal Physiology
Volume294
Issue number3
DOIs
StatePublished - Mar 2008
Externally publishedYes

Keywords

  • Epidermal growth factor receptor
  • Metalloproteinases
  • Renal proximal tubular cells

ASJC Scopus subject areas

  • Physiology
  • Urology

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