Podocyte-specific deletion of integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis

Chiraz El-Aouni, Nadja Herbach, Simone M. Blattner, Anna Henger, Maria P. Rastaldi, George Jarad, Jeffrey H. Miner, Marcus J. Moeller, Rene St.-Arnaud, Shoukat Dedhar, Lawrence B. Holzman, Ruediger Wanke, Matthias Kretzler

Research output: Contribution to journalArticle

Abstract

Alterations in glomerular podocyte cell-cell and cell-matrix contacts are key events in progressive glomerular failure. Integrin-linked kinase (ILK) has been implicated in podocyte cell-matrix interaction and is induced in proteinuria. For evaluation of ILK function in vivo, mice with a Cre-mediated podocyte-specific ILK inactivation were generated. These mice seemed normal at birth but developed progressive focal segmental glomerulosclerosis and died in terminal renal failure. The first ultrastructural lesions that are seen at onset of albuminuria are glomerular basement membrane (GBM) alterations with a significant increase in true harmonic mean GBM thickness. Podocyte foot process effacement and loss of slit diaphragm followed with progression to unselective proteinuria. No significant reduction of slit membrane molecules (podocin and nephrin), key GBM components (fibronectin, laminins, and collagen IV isoforms), or podocyte integrins could be observed at onset of proteinuria. However, α3-integrins were relocalized into a granular pattern along the GBM, consistent with altered integrin-mediated matrix assembly in ILK-deficient podocytes. As the increased GBM thickness precedes structural podocyte lesions and key components of the GBM were expressed at comparable levels to controls, these data suggest an essential role of ILK for the close interconnection of GBM structure and podocyte function.

Original languageEnglish
Pages (from-to)1334-1344
Number of pages11
JournalJournal of the American Society of Nephrology
Volume17
Issue number5
DOIs
Publication statusPublished - May 2006

ASJC Scopus subject areas

  • Nephrology

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    El-Aouni, C., Herbach, N., Blattner, S. M., Henger, A., Rastaldi, M. P., Jarad, G., Miner, J. H., Moeller, M. J., St.-Arnaud, R., Dedhar, S., Holzman, L. B., Wanke, R., & Kretzler, M. (2006). Podocyte-specific deletion of integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis. Journal of the American Society of Nephrology, 17(5), 1334-1344. https://doi.org/10.1681/ASN.2005090921