Determinants of vascular permeability in the kidney glomerulus

被引:98
作者
Hamano, Y
Grunkemeyer, JA
Sudhakar, A
Zeisberg, M
Cosgrove, D
Morello, R
Lee, B
Sugimoto, H
Kalluri, R
机构
[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Program Matrix Biol,Dept Med,Div Gastroenterol, Boston, MA 02215 USA
[2] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Program Matrix Biol, Boston, MA 02215 USA
[3] Boys Town Natl Res Hosp, Gene Express Lab, Omaha, NE 68131 USA
[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
关键词
D O I
10.1074/jbc.M204806200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, alpha-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 alpha3 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 epithelia slit diaphragms lead to a precipitous plasma protein leak.
引用
收藏
页码:31154 / 31162
页数:9
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