Biomechanical strain causes maladaptive gene regulation, contributing to alport glomerular disease

Daniel T. Meehan, Duane Delimont, Linda Cheung, Marisa Zallocchi, Steven C. Sansom, J. David Holzclaw, Velidi Rao, Dominic Cosgrove

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Patients with Alport's syndrome develop a number of pro-inflammatory cytokine and matrix metalloproteinase (MMP) abnormalities that contribute to progressive renal failure. Changes in the composition and structure of the glomerular basement membranes likely alter the biomechanics of cell adhesion and signaling in these patients. To test if enhanced strain on the capillary tuft due to these structural changes contributes to altered gene regulation, we subjected cultured podocytes to cyclic biomechanical strain. There was robust induction of interleukin (IL)-6, along with MMP-3,-9,-10, and-14, but not MMP-2 or-12 by increased strain. Neutralizing antibodies against IL-6 attenuated the strain-mediated induction of MMP-3 and-10. Alport mice treated with a general inhibitor of nitric oxide synthase (L-NAME) developed significant hypertension and increased IL-6 and MMP-3 and-10 in their glomeruli relative to those of normotensive Alport mice. These hypertensive Alport mice also had elevated proteinuria along with more advanced histological and ultrastructural glomerular basement membrane damage. We suggest that MMP and cytokine dysregulation may constitute a maladaptive response to biomechanical strain in the podocytes of Alport patients, thus contributing to glomerular disease initiation and progression.

Original languageEnglish (US)
Pages (from-to)968-976
Number of pages9
JournalKidney International
Volume76
Issue number9
DOIs
StatePublished - Nov 2009

Keywords

  • Alport syndrome
  • Biomechanical strain
  • Podocyte adhesion

ASJC Scopus subject areas

  • Nephrology

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