Determinants of vascular permeability in the kidney glomerulus

Yuki Hamano, James A. Grunkemeyer, Akulapalli Sudhakar, Michael Zeisberg, Dominic Cosgrove, Roy Morello, Brendan Lee, Hikaru Sugimoto, Raghu Kalluri

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

The human kidneys filter 70 liters of blood plasma every day. The hallmark of almost all kidney diseases, whether acquired or genetic, is the leakage of plasma proteins into the urine because of alterations in the glomerular filtration unit of the kidney. In this regard, the human mutations in nephrin, podocin, α-actinin-4, COL4A3, and COL4A5 genes expressed in the glomeruli have been implicated to cause alterations in glomerular filtration apparatus. Nevertheless, the expression of these proteins in relation to each other in mouse models for glomerular vascular leak is unknown. Additionally, within the glomerulus, the central question of whether the primary filtration barrier is the basement membrane or the epithelial slit diaphragm remains ambiguous. Therefore, in this study, we examined the localization and expression of glomerular epithelial slit diaphragm and glomerular basement membrane proteins implicated in glomerular vascular leak using mice deficient in either the α3 chain of type IV collagen, the major constituent of glomerular basement membrane, or LMX1B transcription factor, which regulates the expression of key glomerular type IV collagen genes COL4A3 and COL4A4 or nephrin, a glomerular epithelial slit diaphragm-associated protein. This study demonstrates that decreased expression of slit diaphragm protein, nephrin, correlates with a loss of glomerular filter integrity. Additionally, we demonstrate that defects induced by proteins of glomerular basement membrane lead to an insidious plasma protein leak, whereas the defects induced by proteins in the glomerular epithelial slit diaphragms lead to a precipitous plasma protein leak.

Original languageEnglish (US)
Pages (from-to)31154-31162
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number34
DOIs
StatePublished - Aug 23 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Hamano, Y., Grunkemeyer, J. A., Sudhakar, A., Zeisberg, M., Cosgrove, D., Morello, R., Lee, B., Sugimoto, H., & Kalluri, R. (2002). Determinants of vascular permeability in the kidney glomerulus. Journal of Biological Chemistry, 277(34), 31154-31162. https://doi.org/10.1074/jbc.M204806200