Abstract
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 etidocytosed 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)-κB 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 jasplaktnolide, an F-actin stabilizer, decreased NF-κB 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-κB- 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-κB 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1309-1320 |
| Number of pages | 12 |
| Journal | American Journal of Pathology |
| Volume | 166 |
| Issue number | 5 |
| Publication status | Published - May 2005 |
Fingerprint
ASJC Scopus subject areas
- Pathology and Forensic Medicine
Cite this
In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene : Implication for permselective dysfunction of chronic nephropathies. / Morigi, Marina; Buelli, Simona; Angioletti, Stefania; Zanchi, Cristina; Longaretti, Lorena; Zoja, Carla; Galbusera, Miriam; Gastoldi, Sara; Mundel, Peter; Remuzzi, Giuseppe; Benigni, Ariela.
In: American Journal of Pathology, Vol. 166, No. 5, 05.2005, p. 1309-1320.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene
T2 - Implication for permselective dysfunction of chronic nephropathies
AU - Morigi, Marina
AU - Buelli, Simona
AU - Angioletti, Stefania
AU - Zanchi, Cristina
AU - Longaretti, Lorena
AU - Zoja, Carla
AU - Galbusera, Miriam
AU - Gastoldi, Sara
AU - Mundel, Peter
AU - Remuzzi, Giuseppe
AU - Benigni, Ariela
PY - 2005/5
Y1 - 2005/5
N2 - 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 etidocytosed 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)-κB 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 jasplaktnolide, an F-actin stabilizer, decreased NF-κB 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-κB- 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-κB 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.
AB - 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 etidocytosed 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)-κB 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 jasplaktnolide, an F-actin stabilizer, decreased NF-κB 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-κB- 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-κB 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.
UR - http://www.scopus.com/inward/record.url?scp=20944437139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20944437139&partnerID=8YFLogxK
M3 - Article
C2 - 15855633
AN - SCOPUS:20944437139
VL - 166
SP - 1309
EP - 1320
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 5
ER -