TY - JOUR
T1 - Glomerular filtration is normal in the absence of both agrin and perlecan-heparan sulfate from the glomerular basement membrane
AU - Goldberg, Seth
AU - Harvey, Scott J.
AU - Cunningham, Jeanette
AU - Tryggvason, Karl
AU - Miner, Jeffrey H.
N1 - Funding Information:
Acknowledgements. We thank Jennifer Richardson for mouse genotyp-ing, the Mouse Genetics Core for animal care and the Pulmonary Morphology Core (supported by P01HL029594) for histology services. This work was supported by an American Heart Association Established Investigator Award and NIH grants R01DK064687, R01GM060432 and R01DK078314 to J.H.M., and by grants from the Swedish Medical Research Council, the Knut and Alice Wallenberg Foundation and the Novo Nordisk Foundation to K.T. S.G. was supported by NIH training grant T32DK007126. Valuable technical support was provided by the Washington University Center for Kidney Disease Research (P30DK079333).
PY - 2009/7
Y1 - 2009/7
N2 - Background. For several decades, it has been thought that the glomerular basement membrane (GBM) provides a charge-selective barrier for glomerular filtration. However, recent evidence has presented challenges to this concept: selective removal of heparan sulfate (HS) moieties that impart a negative charge to the GBM causes little if any increase in proteinuria. Removal of agrin, the major GBM HS-proteoglycan (HSPG), from the GBM causes a profound reduction in the glomerular anionic charge without changing the excretion of a negatively charged tracer. Perlecan is another HSPG present in the GBM, as well as in the mesangium and Bowman's capsule, that could potentially contribute to a charge barrier in the absence of agrin.Methods. Here we studied the nature of the glomerular filtration barrier to albumin in mice lacking the HS chains of perlecan either alone or in combination with podocyte-specific loss of agrin.Results. The results show significant reductions in anionic sites within the GBM in perlecan-HS and in perlecan-HSagrin double mutants. Podocyte and overall glomerular architecture were normal, and renal function was normal up to 15 months of age with no measurable proteinuria. Moreover, excretion of a negatively charged Ficoll tracer was unchanged as compared to control mice.Conclusions. These findings cast further doubt upon a critical role for the GBM in charge selectivity.
AB - Background. For several decades, it has been thought that the glomerular basement membrane (GBM) provides a charge-selective barrier for glomerular filtration. However, recent evidence has presented challenges to this concept: selective removal of heparan sulfate (HS) moieties that impart a negative charge to the GBM causes little if any increase in proteinuria. Removal of agrin, the major GBM HS-proteoglycan (HSPG), from the GBM causes a profound reduction in the glomerular anionic charge without changing the excretion of a negatively charged tracer. Perlecan is another HSPG present in the GBM, as well as in the mesangium and Bowman's capsule, that could potentially contribute to a charge barrier in the absence of agrin.Methods. Here we studied the nature of the glomerular filtration barrier to albumin in mice lacking the HS chains of perlecan either alone or in combination with podocyte-specific loss of agrin.Results. The results show significant reductions in anionic sites within the GBM in perlecan-HS and in perlecan-HSagrin double mutants. Podocyte and overall glomerular architecture were normal, and renal function was normal up to 15 months of age with no measurable proteinuria. Moreover, excretion of a negatively charged Ficoll tracer was unchanged as compared to control mice.Conclusions. These findings cast further doubt upon a critical role for the GBM in charge selectivity.
KW - Charge selectivity
KW - Ficoll
KW - Glomerular basement membrane
KW - Glomerular filtration
KW - Perlecan
UR - http://www.scopus.com/inward/record.url?scp=67651089928&partnerID=8YFLogxK
U2 - 10.1093/ndt/gfn758
DO - 10.1093/ndt/gfn758
M3 - Article
C2 - 19144998
AN - SCOPUS:67651089928
SN - 0931-0509
VL - 24
SP - 2044
EP - 2051
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 7
ER -