Inhibition of Protein Glycosylation Causes Renal Dysplasia in the Chick Embryo

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Abstract
The pathogenesis of renal dysplasia, a common congenital renal malformation, remains poorly understood. However, the disease is believed to represent failure of normal renal morphogenesis. Recently, it has been demonstrated that a shift in the composition of the extracellular matrix from an interstitial type to a basement membrane type heralds induction of the renal mesenchyme. In addition, 2 agents that inhibit glycosylation of extracellular matrix glycoconjugates, 6-diazo-5-oxonorleucine and tunicamycin, prevent induction of tubules in vitro. To investigate the relationship between failure of tubulogenesis and renal dysplasia experimentally, we used these inhibitors as potential teratogens and examined the resultant effects of the renal distribution of 2 extracellular matrix constituents: laminin, a basement membrane glycoprotein, and fibronectin, an interstitial glycoprotein. We documented the normal shift in the distribution of laminin and fibronectin during tubulogenesis. Fibronectin, prominent in undifferentiated mesenchyme, tended to disappear during development, while laminin appeared in increasing amounts within differentiating tubules. Renal rudiments (7 to 9 days of incubation) were exposed to tunicamycin, 6-diazo-5-oxo-norleucine or control media in vitro and then they were permitted to develop further as grafts in ovo. In 127 surviving grafts those treated at 8 days of incubation for 48 hours most often were dysplastic: 12 of 18 (67 per cent) tunicamycin versus 3 of 16 (19 per cent) control media (p less than 0.025) and 8 of 13 (62 per cent) 6-diazo-5-oxo-norleucine versus 2 of 16 (12 per cent) control media (p less than 0.025). Most rudiments exposed to 6-diazo-5-oxo-norleucine or tunicamycin for only 24 hours at 8 days of incubation or at 7 or 9 days of incubation were not dysplastic. Finally, 4 chick kidneys with induced dysplasia and 2 fresh surgical specimens with dysplasia were stained for laminin and fibronectin with indirect immunofluorescence and all showed abnormal distributions of both glycoproteins. These results support existing theories that dysplasia is the result of a disruption in normal epithelial-mesenchymal interaction during the induction of renal tubules.