Protease-aktivierte Rezeptoren regulieren Zell-Zell-Kontakte in renalen Podozyten und damit die Permeabilität des glomerulären Filters
Final Report Abstract
Zonulin is a 47kDa protein that is secreted by enterocytes, and serves as a paracrine regulator of small intestine permeability. While the physiological function of this reversible process is not well understood, it has been shown that in patients with Celiac Disease (CD) zonulin levels are elevated in responses to a gluten-rich diet, leading to abnormal paracellular transport and diarrhea. Mechanistically, zonulin binds to protease-activated receptor (PAR) 2 on enterocytes leading to the phosphorylation of zonula occludens (ZO)-1 and the transient disassembly of tight junctions (TJ). Since zonulin has also been described to be elevated in the serum of patients with CD as well as other autoimmune diseases, zonulin could function as a potential circulating modulator of TJs in other tissues. In order to analyze if zonulin can directly affect the podocyte slit diaphragm, a specialized cell-cell junction that contains TJ-proteins, we used the ATI 002 peptide, which resembles zonulin's active PAR2 binding domain. AT1002 treatment of cultured podocytes caused a rearrangement of the actin cytoskeleton accompanied by decreased cell migration, as well as an increase in tyrosine-phosphorylation of ZO-1. Furthermore, in paracellular flux assays, movement of 70kDa dextran particles across podocyte layers was increased in the presence of AT1002. When isolated rat glomeruli where treated with AT1002, albumin permeability was increased. Interestingly, when glomeruli where incubated with serum from patients with FSGS, the elevation of albumin permeability was significantly reduced in the presence of a zonulin blocking antibody or blocking peptide. Finally, when gluten was delivered repetitively by gavage, mice developed mild proteinuria. Taken together, our preliminary data indicate that zonulin increases paracellular transport across podocytes and modulates the selectivity of glomerular filtration. Future studies aim to determine serum zonulin levels in FSGS patients, and urine albumin levels in patients with CD.
Publications
- Zonulin, a novel regulator of glomerular filter permeability? 9th International Podocyte Conference, 2012, Miami, USA
Britta Walter, Cristina Muresan, Karen Lammers, Judith Molina, Sandra Merscher-Gomez, Alessio Fasano, Michele Carraro, Christian Faul
- Zonulin: a novel regulator of glomerular filter permeability? ASN 2012, San Diego, USA
Walter B, Muresan C, Lammers K, Molina J, Merscher-Gomez S, Fasano A, Carraro M, Faul C
