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2017 ; 114
(11
): 2958-2963
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Permeation of macromolecules into the renal glomerular basement membrane and
capture by the tubules
#MMPMID28246329
Lawrence MG
; Altenburg MK
; Sanford R
; Willett JD
; Bleasdale B
; Ballou B
; Wilder J
; Li F
; Miner JH
; Berg UB
; Smithies O
Proc Natl Acad Sci U S A
2017[Mar]; 114
(11
): 2958-2963
PMID28246329
show ga
How the kidney prevents urinary excretion of plasma proteins continues to be
debated. Here, using unfixed whole-mount mouse kidneys, we show that
fluorescent-tagged proteins and neutral dextrans permeate into the glomerular
basement membrane (GBM), in general agreement with Ogston's 1958 equation
describing how permeation into gels is related to molecular size.
Electron-microscopic analyses of kidneys fixed seconds to hours after injecting
gold-tagged albumin, negatively charged gold nanoparticles, and stable
oligoclusters of gold nanoparticles show that permeation into the lamina densa of
the GBM is size-sensitive. Nanoparticles comparable in size with IgG dimers do
not permeate into it. IgG monomer-sized particles permeate to some extent.
Albumin-sized particles permeate extensively into the lamina densa. Particles
traversing the lamina densa tend to accumulate upstream of the podocyte
glycocalyx that spans the slit, but none are observed upstream of the slit
diaphragm. At low concentrations, ovalbumin-sized nanoparticles reach the primary
filtrate, are captured by proximal tubule cells, and are endocytosed. At higher
concentrations, tubular capture is saturated, and they reach the urine. In mouse
models of Pierson's or Alport's proteinuric syndromes resulting from defects in
GBM structural proteins (laminin ?2 or collagen ?3 IV), the GBM is irregularly
swollen, the lamina densa is absent, and permeation is increased. Our
observations indicate that size-dependent permeation into the lamina densa of the
GBM and the podocyte glycocalyx, together with saturable tubular capture,
determines which macromolecules reach the urine without the need to invoke direct
size selection by the slit diaphragm.