A molecular mechanism explaining albuminuria in kidney disease.

Nature Metabolism
Linus ButtThomas Benzing

Abstract

Mammalian kidneys constantly filter large amounts of liquid, with almost complete retention of albumin and other macromolecules in the plasma. Breakdown of the three-layered renal filtration barrier results in loss of albumin into urine (albuminuria) across the wall of small renal capillaries, and is a leading cause of chronic kidney disease. However, exactly how the renal filter works and why its permeability is altered in kidney diseases is poorly understood. Here we show that the permeability of the renal filter is modulated through compression of the capillary wall. We collect morphometric data prior to and after onset of albuminuria in a mouse model equivalent to a human genetic disease affecting the renal filtration barrier. Combining quantitative analyses with mathematical modelling, we demonstrate that morphological alterations of the glomerular filtration barrier lead to reduced compressive forces that counteract filtration pressure, thereby resulting in capillary dilatation, and ultimately albuminuria. Our results reveal distinct functions of the different layers of the filtration barrier and expand the molecular understanding of defective renal filtration in chronic kidney disease.

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Citations

Aug 26, 2020·Nature Reviews. Nephrology·Richard W NaylorRachel Lennon
Jul 1, 2020·Nature Reviews. Nephrology·Marcus J Moeller, Arnaldo Chia-Gil
Nov 5, 2020·Kidney International·Hiroyuki YamadaKatsuhiko Asanuma
Nov 15, 2020·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Sanja Sever
Jan 31, 2021·Journal of the American Society of Nephrology : JASN·Manuel RoggChristoph Schell
Apr 15, 2021·The New England Journal of Medicine·Thomas Benzing, David Salant
Jun 25, 2021·Advanced Science·Joanne X ShenVolker M Lauschke
Jul 16, 2021·Nature Reviews. Drug Discovery·Ilse S Daehn, Jeremy S Duffield
Jul 27, 2021·EMBO Reports·Jörg HöhfeldBettina Warscheid
Jul 29, 2021·The New England Journal of Medicine·Aurelie EdwardsThomas Benzing
Aug 2, 2021·Kidney International·Linus ButtThomas Benzing
Oct 7, 2021·Annual Review of Cell and Developmental Biology·Joe Chin-Hun Kuo, Matthew J Paszek

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Datasets Mentioned

BETA
GM500m
PXD018326

Methods Mentioned

BETA
super-resolution microscopy
confocal microscopy
electrophoresis
genotyping
in vitro transcription
biopsies
PCR
ELISA
blood draw
transmission electron microscopy

Key Resources (RRID) Mentioned

Addgene_48138
AB_2043201
AB_2307443
AB_261982
AB_2534723
AB_2534711

Software Mentioned

Excel
ImageJ
Fiji
GraphPad Prism
MaxQuant
Perseus

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