Heparin-Binding EGF in Autosomal Recessive PKD

Case Western Reserve University, Cleveland OH

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Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of morbidity and mortality in children and adolescents. Major recent advances have identified the causative gene, PKHD1 and the abnormal protein product, fibrocystin. A key feature of most forms of PKD is overexpression and abnormal localization of epidermal growth factor (EGF)-related growth factors and their shared receptor, EGF receptor (EGFR). Inhibitors of EGFR or tumor necrosis factor-alpha converting enzyme (TACE), a metalloproteinase that mediates cleavage of EGF-related growth factors to produce the soluble forms, ameliorates cystic kidney disease in several PKD animal models. However, EGFR inhibition does not ameliorate cystic kidney disease in the PCK rat, which harbors a mutation in rat homologue of PKDH1. We now show that heparinbinding EGF (HB-EGF), an EGF-related growth factor, and its receptor, ErbB4, are overexpressed and mislocalized in the collecting tubule (CT) cysts of kidneys of both the PCK rat and the bpk mouse models of ARPKD. We also show that HB-EGF is upregulated in cultured CT cells. These shared features suggest that HB-EGF/ErbB4 may be the most relevant growth factor pathway in ARPKD pathogenesis. HB-EGF is upregulated by the MAP kinase, ERK , which is a target of cyclic AMP, a second messenger that is upregulated in PKD. The hypothesis is that in cystic epithelium, HB-EGF and ErbB4 overexpression and mislocalization are induced by cAMP-dependent ERK 1/2 activation. These signaling molecules also stimulate activation of TACE, and resultant HB-EGF shedding thereby promoting tubular epithelial cell proliferation, induction of other EGF-related growth factors and further ERK 1/2 activation. The specific aims are (1) To determine the requirement for the HB-EGF/ErbB4 axis in cyst development and disease progression in the bpk model of ARPKD; (2) To define the role of TACE in the pathogenesis of cystic kidney in disease in ARPKD; and (3) To delineate the role of cAMP and ERK 1/2 in mediating HB-EGF overexpression in cystic epithelia. The overall goals of this research are to delineate that mediators and signaling pathways that link upstream events, such as cAMP and ERK 1/2 activation, to HB-EGF/ErbB4 overexpression and cystogenic processes such as cell proliferation. These studies will provide important insights into ARPKD disease pathogenesis and may identify potential new therapeutic targets.