α1β1 Integrin/rac1-dependent mesangial invasion of glomerular capillaries in alport syndrome

Marisa L Zallocchi, Brianna M. Johnson, Daniel T. Meehan, Duane Delimont, Dominic E Cosgrove

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Alport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. l-NAME salt-induced hypertension accelerated mesangial cell process invasion. Cultured mesangial cells showed reduced migratory potential when treated with either integrin-linked kinase inhibitor or Rac1 inhibitor, or by deletion of integrin α1. Treatment of Alport mice with Rac1 inhibitor or deletion of integrin α1 reduced mesangial cell process invasion of the glomerular capillary tuft. Laminin α2-deficient Alport mice show reduced mesangial process invasion, and cultured laminin α2-null cells showed reduced migratory potential, indicating a functional role for mesangial laminins in progression of Alport glomerular pathogenesis. Collectively, these findings predict a role for biomechanical insult in the induction of integrin α1β1-dependent Rac1-mediated mesangial cell process invasion of the glomerular capillary tuft as an initiation mechanism of Alport glomerular pathology.

Original languageEnglish (US)
Pages (from-to)1269-1280
Number of pages12
JournalAmerican Journal of Pathology
Volume183
Issue number4
DOIs
StatePublished - Oct 1 2013

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Hereditary Nephritis
Laminin
Integrins
Mesangial Cells
Null Lymphocytes
Glomerular Basement Membrane
Collagen Type IV
Glomerulonephritis
Hearing Loss
Knockout Mice
Cultured Cells
Salts
Pathology
Hypertension
Mutation
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

α1β1 Integrin/rac1-dependent mesangial invasion of glomerular capillaries in alport syndrome. / Zallocchi, Marisa L; Johnson, Brianna M.; Meehan, Daniel T.; Delimont, Duane; Cosgrove, Dominic E.

In: American Journal of Pathology, Vol. 183, No. 4, 01.10.2013, p. 1269-1280.

Research output: Contribution to journalArticle

Zallocchi, Marisa L ; Johnson, Brianna M. ; Meehan, Daniel T. ; Delimont, Duane ; Cosgrove, Dominic E. / α1β1 Integrin/rac1-dependent mesangial invasion of glomerular capillaries in alport syndrome. In: American Journal of Pathology. 2013 ; Vol. 183, No. 4. pp. 1269-1280.
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