Podocyte-specific deletion of NDST1, a key enzyme in the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in podocyte organization in vivo.
Heparan sulfate proteoglycans have been shown to modulate podocyte adhesion to--and pedicel organization on--the glomerular basement membrane. Recent studies showed that foot process effacement developed in a mutant mouse model whose podocytes were unable to assemble heparan sulfate glycosaminoglycan chains. This study, a further refinement, explored the role of heparan N-sulfation on podocyte behavior. A novel mutant mouse (Ndst1(-/-)) was developed, having podocyte-specific deletion of Ndst1, the enzyme responsible for N-sulfation of heparan sulfate chains. Podocytes having this mutation had foot process effacement and abnormal adhesion to Bowman's capsule. Although glomerular hypertrophy did develop in the kidneys of mutant animals, mesangial expansion was not seen. The lack of heparan N-sulfation did not affect the expression of agrin or perlecan proteoglycan core proteins. Loss of N-sulfation did not result in significant proteinuria, but the increase in the albumin/creatinine ratio was coincident with the development of the enlarged lysosomes in the proximal tubules. Thus, although the renal phenotype of the Ndst1(-/-) mouse is mild, the data show that heparan chain N-sulfation plays a key role in podocyte organization.
Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, Louisiana, USA.
Terrel
T
Sugar
Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana, USA.
Deborah J
DJ
Wassenhove-McCarthy
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, San Diego, California, USA.
Jeffrey D
JD
Esko
Department of Biochemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Toin H
TH
van Kuppevelt
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Lawrence
L
Holzman
1] Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, Louisiana, USA [2] Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana, USA.
Kevin J
KJ
McCarthy
D018171:Agrin / Q000378:metabolism; D000419:Albuminuria / Q000235:genetics / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005838:Genotype; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006984:Hypertrophy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D018171:Agrin; D019812:Heparan Sulfate Proteoglycans; C071927:perlecan; D015238:Sulfotransferases; C021350:heparitin sulfotransferase