Glomerular filtration is normal in the absence of both agrin and perlecan-heparan sulfate from the glomerular basement membrane.

Full Abstract

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-HS/agrin 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.

Author information

Author/s: Goldberg, Seth (S); Harvey, Scott J (SJ); Cunningham, Jeanette (J); Tryggvason, Karl (K); Miner, Jeffrey H (JH);

Affiliation: Renal Division, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.

Grants: P01HL029594 (Agency:NHLBI NIH HHS) ; P30DK079333 (Agency:NIDDK NIH HHS) ; R01 DK064687-04 (Agency:NIDDK NIH HHS) ; R01 DK078314-01A1 (Agency:NIDDK NIH HHS) ; R01 GM060432-06 (Agency:NIGMS NIH HHS) ; R01 GM060432-07 (Agency:NIGMS NIH HHS) ; R01 GM060432-08 (Agency:NIGMS NIH HHS) ; R01DK064687 (Agency:NIDDK NIH HHS) ; R01DK078314 (Agency:NIDDK NIH HHS) ; R01GM060432 (Agency:NIGMS NIH HHS) ; T32DK007126 (Agency:NIDDK NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant), published in England. (Language: eng)

Reference: 2009-Jul; vol 24 (issue 7) : pp 2044-51

Dates: Created 2009/06/22; Completed 2009/08/24;

PMID: 19144998, status: MEDLINE (last retrieval date: 8/24/2009, IMS Date: )

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