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Laminin Compensation in Collagen 3(IV) Knockout (Alport) Glomeruli Contributes to Permeability Defects

Dale R. Abrahamson^*, Kathryn Isom^*, Eileen Roach^*, Larysa Stroganova^*, Adrian Zelenchuk^*, Jeffrey H. Miner and Patricia L. St. John^*

^* Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas; and Renal Division, Department of Internal Medicine, Washington University, St. Louis, Missouri

Correspondence: Dr. Dale R. Abrahamson, Department of Anatomy and Cell Biology, University of Kansas Medical Center, MS 3038, 3901 Rainbow Boulevard, Kansas City, KS 66160. Phone: 913-588-7000; Fax: 913-588-2710; E-mail: dabrahamson{at}kumc.edu

Received for publication March 17, 2007. Accepted for publication May 14, 2007.

Alport disease is caused by mutations in genes encoding the 3, 4, or 5 chains of type IV collagen, which form the collagenous network of mature glomerular basement membrane (GBM). In the absence of 3, 4, 5 (IV) collagen, 1, 2 (IV) collagen persists, which ordinarily is found only in GBM of developing kidney. In addition to dysregulation of collagen IV, Alport GBM contains aberrant laminins, which may contribute to the progressive GBM thickening and splitting, proteinuria, and renal failure seen in this disorder. This study sought to characterize further the laminin dysregulation in collagen 3(IV) knockout mice, a model of Alport disease. With the use of confocal microscopy, laminin 1 and 5 abundance was quantified, and it was found that they co-distributed in significantly large amounts in areas of GBM thickening. In addition, labeling of entire glomeruli for laminin 5 was significantly greater in Alport mice than in wild-type siblings. Reverse transcriptase–PCR from isolated glomeruli demonstrated significantly more laminin 5 mRNA in Alport mice than in wild-type controls, indicating upregulated transcription of Lama5. For testing glomerular barrier function, ferritin was injected into 2-wk-old Alport and control mice, and GBM was examined by electron microscopy. Highest ferritin levels were seen in Alport GBM thickenings beneath effaced podocyte foot processes, but morphologically normal GBM was significantly permeable as well. We concluded that (1) ultrastructurally normal Alport GBM residing beneath differentiated podocyte foot processes is inherently and abnormally permeable, and (2) upregulation of Lama5 transcription and concentration of laminin 1 and 5 within Alport GBM thickenings contribute to abnormal permeabilities.

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