Bradykinin decreases podocyte permeability through ADAM17-dependent epidermal growth factor receptor activation and zonula occludens-1 rearrangement.
Recent data show that increases in bradykinin (BK) concentration contribute to the beneficial effects of angiotensin-converting enzyme inhibitor (ACEI) treatment in chronic kidney disease. However, the possible role of BK in attenuated proteinuria, often seen in ACEI-treated patients, is not well studied. Here, we report that BK decreases mouse podocyte permeability through rearrangement of the tight junction protein zonula occludens-1 (ZO-1) and identify some of the major signaling events leading to permeability change. We show that BK2 receptor (BK2R) stimulation transactivates the epidermal growth factor receptor (EGFR). EGFR transactivation is mediated by a disintegrin and metalloenzyme (ADAM) family members, which are required for both extracellular signal-regulated kinase (ERK) and EGFR activation by BK. Using a gene-silencing approach we observed that both BK-induced ERK activation and BK-induced permeability decrease in podocytes is attenuated by ADAM17 down-regulation, and we identified epiregulin (ER) as the EGFR ligand participating in ADAM-dependent BK2R-EGFR cross-talk. EGFR inhibition attenuated both ZO-1 rearrangement and BK-induced permeability decreases in podocyte. We propose that ZO-1 redistribution is an important element of BK-induced permeability change and the signaling events involved in ZO-1 rearrangement include transactivation of the EGFR via ADAM17 activation and ER shedding. Our data indicate that ADAM17 and the EGFR may be potential novel therapeutic targets in diabetic nephropathy and other chronic kidney diseases.
Dey
Mamon
M
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Baldys
Aleksander
A
Sumter
Dezmond B
DB
Göoz
Pal
P
Luttrell
Louis M
LM
Raymond
John R
JR
Göoz
Monika
M
D051722:ADAM Proteins / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D066246:ErbB Receptors / Q000819:agonists*; D007678:Kidney Glomerulus / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects*; D034622:RNA Interference; D020239:Receptor Cross-Talk; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects; D062826:Zonula Occludens-1 Protein
D008565:Membrane Proteins; D010750:Phosphoproteins; D043782:Receptor, Bradykinin B2; D043562:Receptors, G-Protein-Coupled; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D001920:Bradykinin