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. 2009 Jul;20(7):1471-9.
doi: 10.1681/ASN.2008101086. Epub 2009 May 7.

Cellular origins of type IV collagen networks in developing glomeruli

Dale R Abrahamson  1 , Billy G Hudson, Larysa Stroganova, Dorin-Bogdan Borza, Patricia L St John
Affiliations

Cellular origins of type IV collagen networks in developing glomeruli

Dale R Abrahamson et al. J Am Soc Nephrol. 2009 Jul.

Abstract

Laminin and type IV collagen composition of the glomerular basement membrane changes during glomerular development and maturation. Although it is known that both glomerular endothelial cells and podocytes produce different laminin isoforms at the appropriate stages of development, the cellular origins for the different type IV collagen heterotrimers that appear during development are unknown. Here, immunoelectron microscopy demonstrated that endothelial cells, mesangial cells, and podocytes of immature glomeruli synthesize collagen alpha 1 alpha 2 alpha1(IV). However, intracellular labeling revealed that podocytes, but not endothelial or mesangial cells, contain collagen alpha 3 alpha 4 alpha 5(IV). To evaluate the origins of collagen IV further, we transplanted embryonic kidneys from Col4a3-null mutants (Alport mice) into kidneys of newborn, wildtype mice. Hybrid glomeruli within grafts containing numerous host-derived, wildtype endothelial cells never expressed collagen alpha 3 alpha 4 alpha 5(IV). Finally, confocal microscopy of glomeruli from infant Alport mice that had been dually labeled with anti-collagen alpha 5(IV) and the podocyte marker anti-GLEPP1 showed immunolabeling exclusively within podocytes. Together, these results indicate that collagen alpha 3 alpha 4 alpha 5(IV) originates solely from podocytes; therefore, glomerular Alport disease is a genetic defect that manifests specifically within this cell type.

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Figures

Figure 1.
Figure 1.
Postfixation immunoperoxidase labeling of developing glomerulus with anti-α1α2α1 collagen (IV). Both the GBM and Boman's capsule (BC in inset) basement membranes contain heavy, electron dense peroxidase reaction product. Note intracellular labeling of biosynthetic organelles in glomerular endothelial (En) cells (arrows) and podocytes (Po, arrowheads).
Figure 2.
Figure 2.
Postfixation immunolabeling of developing glomerulus with anti-α1α2α1 collagen (IV). Immunoperoxidase labeling is observed intracellularly within mesangial cells (arrows, Me) and developing mesangial matrix (arrowheads), as well as in the GBM. En: Endothelium.
Figure 3.
Figure 3.
Postfixation immunolabeling of developing glomerular capillary with anti-α3α4α5 collagen (IV). Note peroxidase labeling of GBM and biosynthetic organelles within podocytes (arrowheads, Po), and absence of label within the endothelium (En).
Figure 4.
Figure 4.
ections showing grafts of Alport metanephroi into ROSA26 host kidneys. (A) Section developed for β-galactosidase activity to show LacZ transgene expression (blue). Note presence of hybrid glomeruli (Hy) containing host-derived endothelial cells. (B) Serial section immunolabeled with anti-collagen α1α2α1(IV). GBMs within hybrid glomeruli (Hy) and host glomeruli (HG) are positive, as are tubular basement membranes in host and graft tissue. (C) Same section as in (B), but immunolabeled with anti-collagen α3α4α5(IV). Only GBMs in host glomeruli (HG) and a few tubular basement membranes are labeled; hybrid glomeruli (Hy) and tubules within graft tissue are negative.
Figure 5.
Figure 5.
Electron microscopy of kidneys developed for the dual localization of anti-collagen α3α4α5(IV)-HRP and LacZ expression. (A) Host glomerulus contains peroxidase reaction product in the GBM and β-galactosidase reaction product (arrows) on membranes of endothelial cells (En) and podocytes (Po). (B) Hybrid glomerulus within graft lacks peroxidase reaction product in GBM and shows β-galactosidase reaction product (arrows) only on endothelial cells; podocytes are negative.
Figure 6.
Figure 6.
Sections from graft of wildtype metanephroi into Alport/ROSA26 host. (A) Section developed for LacZ expression showing hybrid glomeruli within graft (arrows) containing host-derived, Alport/LacZ endothelial cells. (B) Section dually immunolabeled with anti-collagen α1α2α1(IV) (red) and anti-collagen α3α4α5(green) showing expression of α3α4α5(IV) in hybrid GBM.
Figure 7.
Figure 7.
Section of developing Alport glomeruli immunolabeled with the podocyte plasma membrane marker, anti-GLEPP1 (A), and anti-collagen α5(IV) (B). Merged image shows intracellular labeling for anti-collagen α5(IV) within podocytes exclusively.
Figure 8.
Figure 8.
Diagram showing development of the glomerular capillary wall, stages of GBM assembly, and cellular origins of different laminin isoforms. Both endothelial cells and podocytes produce laminin α1 and β1, and then α5 and β2. Similarly, both cell types produce the collagen α1α2α1(IV) network. By contrast, the collagen α3α4α5(IV) network originates solely from podocytes. (Redrawn from ref. 4).
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