Loss of heparan sulfate glycosaminoglycan assembly in podocytes does not lead to proteinuria.
Podocytes synthesize the majority of the glomerular basement membrane components with some contribution from the glomerular capillary endothelial cells. The anionic charge of heparan sulfate proteoglycans is conferred by covalently attached heparan sulfate glycosaminoglycans and these are thought to provide critical charge selectivity to the glomerular basement membrane for ultrafiltration. One key component in herparan sulfate glycosaminoglycan assembly is the Ext1 gene product encoding a subunit of heparan sulfate co-polymerase. Here we knocked out Ext1 gene expression in podocytes halting polymerization of heparin sulfate glycosaminoglycans on the proteoglycan core proteins secreted by podocytes. Glomerular development occurred normally in these knockout animals but changes in podocyte morphology, such as foot process effacement, were seen as early as 1 month after birth. Immunohistochemical analysis showed a significant decrease in heparan sulfate glycosaminoglycans confirmed by ultrastructural studies using polyethyleneimine staining. Despite podocyte abnormalities and loss of heparan sulfate glycosaminoglycans, severe albuminuria did not develop in the knockout mice. We show that the presence of podocyte-secreted heparan sulfate glycosaminoglycans is not absolutely necessary to limit albuminuria suggesting the existence of other mechanisms that limit albuminuria. Heparan sulfate glycosaminoglycans appear to have functions that control podocyte behavior rather than be primarily an ultrafiltration barrier.
Chen
Shoujun
S
1Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Wassenhove-McCarthy
Deborah J
DJ
Yamaguchi
Yu
Y
Holzman
Lawrence B
LB
van Kuppevelt
Toin H
TH
Jenniskens
Guido J
GJ
Wijnhoven
Tessa J
TJ
Woods
Ann C
AC
McCarthy
Kevin J
KJ
D000419:Albuminuria; D000818:Animals; D006025:Glycosaminoglycans; D006497:Heparan Sulfate / Q000096:biosynthesis / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000209:etiology*; D000099058:Exostosin 1
D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1