Published online before print May 31, 2007

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(American Journal of Pathology. 2007;171:139-152.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061116

Disruption of Glomerular Basement Membrane Charge through Podocyte-Specific Mutation of Agrin Does Not Alter Glomerular Permselectivity

Scott J. Harvey^*, George Jarad^*, Jeanette Cunningham^*, Angelique L. Rops, Johan van der Vlag, Jo H. Berden, Marcus J. Moeller, Lawrence B. Holzman, Robert W. Burgess^¶ and Jeffrey H. Miner^*||

From the Renal Division,^* and the Department of Cell Biology and Physiology,^|| Washington University School of Medicine, St. Louis, Missouri; the Division of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; the Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and The Jackson Laboratory,^¶ Bar Harbor, Maine

Glomerular charge selectivity has been attributed to anionic heparan sulfate proteoglycans (HSPGs) in the glomerular basement membrane (GBM). Agrin is the predominant GBM-HSPG, but evidence that it contributes to the charge barrier is lacking, because newborn agrin-deficient mice die from neuromuscular defects. To study agrin in adult kidney, a new conditional allele was used to generate podocyte-specific knockouts. Mutants were viable and displayed no renal histopathology up to 9 months of age. Perlecan, a HSPG normally confined to the mesangium in mature glomeruli, did not appear in the mutant GBM, which lacked heparan sulfate. Moreover, GBM agrin was found to be derived primarily from podocytes. Polyethyleneimine labeling of fetal kidneys revealed anionic sites along both laminae rarae of the GBM that became most prominent along the subepithelial aspect at maturity; labeling was greatly reduced along the subepithelial aspect in agrin-deficient and conditional knockout mice. Despite this severe charge disruption, the glomerular filtration barrier was not compromised, even when challenged with bovine serum albumin overload. We conclude that agrin is not required for establishment or maintenance of GBM architecture. Although agrin contributes significantly to the anionic charge to the GBM, both it and its charge are not needed for glomerular permselectivity. This calls into question whether charge selectivity is a feature of the GBM.

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