Role of ADAM17 in bradykinin‐induced EGF receptor activation in glomerular podocytes

Abstract

Beneficial effect of ACE inhibitors was attributed partially by upregulating bradykinin (BK) production. We have shown previously that BK cross‐activates the epidermal growth factor receptor (EGFR) and decreases albumin permeability of mouse podocyte monolayer. We hypothesized that the crosstalk between BK receptor (BKR) and EGFR through a metalloenzyme‐disintegrin (possibly through ADAM17) is responsible for the permeability change in the podocytes. We treated human and mouse podocytes with 10−10‐10−6 M BK and measured ERK activation as a read‐out of the inter‐receptor crosstalk. We found maximum activation of ERK1/2 at 10 min by 10−8 M BK. We pretreated the cells for 30 min with 100 nM AG1478 (inhibitor of EGFR) or 10 µM GM6001 (inhibitor for metalloenzymes) followed by BK treatment and found that ERK1/2 phosphorylation was inhibited. To identify the metalloenzyme involved in this process we transfected the podocytes with small interfering RNA against ADAM17. After successfully silencing the enzyme expression we found that BK induced ERK1/2 activation was attenuated. We conclude that (1) ADAM17 is involved in the crosstalk between BKR and EGFR; (2) ADAM17 is a potential contributor to BK‐induced permeability changes and a potential therapeutic target in kidney fibrosis.