Expression of amphiregulin in various models of polycystic kidney disease (690.1)

Abstract

In polycystic kidney disease (PKD) there is the continual expansion of cysts throughout the time course of this disease. The mechanisms that control the rate of cystic growth are not fully known. In PKD, the epidermal growth factor (EGF) receptor is mislocalized to the apical membrane of epithelial cells that line cystic structures. The findings that cystic fluid contains various hormones and signaling molecules further suggests that growth factors may play a role in regulation of cystic growth. The purpose of this study was to determine which EGF receptor dependent growth factors are elevated in PKD. Growth factors from human cystic fluid and mouse models of PKD were measured with an Elisa assay and RT‐PCR. Amphiregulin (Areg), epiregulin (Ereg), transforming growth factor alpha (TGFα), heparin binding EGF (HBegf) and egf were measured. In the IFT88 knockout mouse model where cilia are deleted, there was a four‐fold increase in Areg mRNA expression in mice that lacked cilia compared to mice with cilia. All other growth factors were the same between cilia minus versus cilia plus mice. In mice with a knockout of polycystin 2 there was a 5 fold increase in only Areg compared to mice with polycystin 2. In mice that lacked polycystin 1 there was 3 fold increase in Areg and an 8 fold increase in Ereg. Other growth factors were unchanged by the presence or absence of these proteins that cause autosomal dominant PKD (ADPKD). In fluid collected from individual cysts from human ADPKD kidneys we found that Areg concentration varied between 49 to 250 pg\ml and also varied between cysts from the same kidney. These results suggest that Areg and possibility Ereg may play a role in cystogenesis in PKD.Grant Funding Source: P30DK074038 and VA Merit