Cellular origins of type IV collagen networks in developing glomeruli.
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.
Abrahamson
Dale R
DR
Department of Anatomy and Cell Biology, The Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 3038, Kansas City, KS 66160, USA. dabrahamson@kumc.edu
Hudson
Billy G
BG
Stroganova
Larysa
L
Borza
Dorin-Bogdan
DB
St John
Patricia L
PL
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure
D001324:Autoantigens; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain