(American Journal of Pathology. 2005;166:1309-1320.)
© 2005 American Society for Investigative Pathology
In Response to Protein Load Podocytes Reorganize Cytoskeleton and Modulate Endothelin-1 Gene
Implication for Permselective Dysfunction of Chronic Nephropathies
Marina Morigi*,
Simona Buelli*,
Stefania Angioletti*,
Cristina Zanchi*,
Lorena Longaretti*,
Carla Zoja*,
Miriam Galbusera*,
Sara Gastoldi*,
Peter Mundel
,
Giuseppe Remuzzi*
and
Ariela Benigni*
From the ‘Mario Negri’ Institute for Pharmacological Research,* Bergamo, Italy; the Division of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy; and the Department of Medicine, Albert Einstein College of Medicine, New York, New York
Effacement of podocyte foot processes occurs in many proteinuric nephropathies and is accompanied by rearrangement of the actin cytoskeleton. Here, we studied whether protein overload affects intracellular pathways, leading to cytoskeletal architecture changes and ultimately to podocyte dysfunction. Mouse podocytes bound and endocytosed both albumin and IgG via receptor-specific mechanisms. Protein overload caused redistribution of F-actin fibers instrumental to up-regulation of the prepro-endothelin (ET)-1 gene and production of the corresponding peptide. Increased DNA-binding activity for nuclear factor (NF)-
B and Ap-1 nuclear proteins was measured in nuclear extracts of podocytes exposed to excess proteins. Both Y27632, which inhibits Rho kinase-dependent stress fiber formation, and jasplakinolide, an F-actin stabilizer, decreased NF-B and Ap-1 activity and reduced ET-1 expression. This suggested a role for the cytoskeleton, through activated Rho, in the regulation of the ET-1 peptide. Focal adhesion kinase (FAK), an integrin-associated nonreceptor tyrosine kinase, was phosphorylated by albumin treatment via Rho kinase-triggered actin reorganization. FAK activation led to NF-B- and Ap-1-dependent ET-1 expression. These data suggest that reorganization of the actin cytoskeletal network in response to protein load is implicated in modulation of the ET-1 gene via Rho kinase-dependent FAK activation of NF-B and Ap-1 in differentiated podocytes. Increased ET-1 generation might alter glomerular permselectivity and amplify the noxious effect of protein overload on dysfunctional podocytes.
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Copyright © 2005 by the American Society for Investigative Pathology.
