Partial rescue of glomerular laminin α5 mutations by wild-type endothelia produce hybrid glomeruli

Dale R. Abrahamson, Patricia L. St. John, Kathryn Isom, Barry Robert, Jeffrey H. Miner

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Both endothelial cells and podocytes are sources for laminin α1 at the inception of glomerulogenesis and then for laminin α5 during glomerular maturation. Why glomerular basement membranes (GBM) undergo laminin transitions is unknown, but this may dictate glomerular morphogenesis. In mice that genetically lack laminin α5, laminin α5β2γ1 is not assembled, vascularized glomeruli fail to form, and animals die at midgestation with neural tube closure and placental deficits. It was previously shown that renal cortices of newborn mice contain endothelial progenitors (angioblasts) and that when embryonic day 12 kidneys are transplanted into newborn kidney, hybrid glomeruli (host-derived endothelium and donor-derived podocytes) result. Reasoning that host endothelium may correct the glomerular phenotype that is seen in laminin α5 mutants, α5 null embryonic day 12 metanephroi were grafted into wild-type newborn kidney. Hybrid glomeruli were identified in grafts by expression of a host-specific LacZ lineage marker. Labeling of glomerular hybrid GBM with chain-specific antibodies showed a markedly stratified distribution of laminins: α5 was found only on the inner endothelial half of GBM, whereas α1 located to outer layers beneath mutant podocytes. For measurement of the contribution of host endothelium to hybrid GBM, immunofluorescent signals for laminin α5 were quantified: Hybrid GBM contained approximately 50% the normal α5 complement as wild-type GBM. Electron microscopy of glomerular hybrids showed vascularization, but podocyte foot processes were absent. It was concluded that (1) endothelial and podocyte-derived laminins remain tethered to their cellular origin, (2) developing endothelial cells contribute large amounts of GBM laminins, and (3) podocyte foot process differentiation may require direct exposure to laminin α5.

Original languageEnglish
Pages (from-to)2285-2293
Number of pages9
JournalJournal of the American Society of Nephrology
Volume18
Issue number8
DOIs
StatePublished - Aug 2007

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