Mechanical forces and TGFβ1 reduce podocyte adhesion through α3β1 integrin downregulation
2009
Background. Podocyturia is a marker of diabetic nephropathy, apossibledeterminant ofitsprogressionandapowerful risk factor for cardiovascular disease. A reduction in podocyte adhesion to the glomerular basement membrane (GBM)viadownregulationof α3β1integrinexpression,the main podocyte anchoring dimer to the GBM, may represent one of the mechanisms of podocyturia in glomerular disease. This study investigated the role of mechanical forces and transforming growth factor beta1 (TGFβ1) in podocyte adhesion and integrin expression. Methods. Conditionally immortalized murine podocytes were exposed to mechanical stretch and/or TGFβ1 for 48 h. Podocyte adhesion, apoptosis and α3β1 integrin expression were assessed. Results.StretchandTGFβ1significantlyreducedpodocyte adhesionand α3β1integrinexpression,eventsparalleledby increasedapoptosis.Blockadeof β1integrin,withaspecific antibody, demonstrated a reduced podocyte adhesion indicating that β1 integrin downregulation was required for the loss of podocyte adhesion. This was linked to an increase in podocyte apoptosis. The role of apoptosis in podocyte adhesion was further investigated using caspase-3 inhibitors. Podocyte apoptosis inhibition did not affect stretch- and TGFβ1-mediated integrin downregulation and the loss of podocyte adhesion, suggesting that α3β1 integrin downregulation is sufficient to alter cell adhesion. Although stretch significantly increased podocyte TGFβ type I, II and III receptors but not podocyte TGFβ1 secretion, the combination of stretch and TGFβ1 did not show any additive or synergistic effects on podocyte adhesion and α3β 1i ntegrin expression. Conclusions. These results suggest that downregulation of α3β1 integrin expression, by mechanical forces or TGFβ1, is per se sufficient to reduce podocyte adhesion. Apoptosis may represent a parallel important determinant of the podocyte loss from the GBM.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
57
References
71
Citations
NaN
KQI