Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome

Journal of the American Society of Nephrology : JASN
Meei-Hua LinJeffrey H Miner

Abstract

Background Laminin α5β2γ1 (LM-521) is a major component of the GBM. Mutations in LAMB2 that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of Lamb2 mutant mice and restore glomerular permselectivity.Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2-/- pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture.Results Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the fo...Continue Reading

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Citations

Apr 14, 2018·Journal of the American Society of Nephrology : JASN·Alda Tufro
Feb 7, 2019·American Journal of Physiology. Renal Physiology·Steven D FunkJeffrey H Miner
Jul 22, 2019·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Maria Lucia AngelottiPaola Romagnani
Oct 12, 2018·Stem Cells Translational Medicine·Julia MarchequeLaura Perin
Jul 28, 2018·Frontiers in Endocrinology·Florian SiegeristNicole Endlich
Aug 26, 2020·Nature Reviews. Nephrology·Richard W NaylorRachel Lennon
Sep 20, 2020·Nature Reviews. Nephrology·Suman RanjitMoshe Levi
Dec 15, 2018·Physiological Reports·Tilman MüllerDaniel Batlle
Apr 16, 2021·Metabolism: Clinical and Experimental·Anna GoddiRonald N Cohen
Apr 27, 2021·European Journal of Pharmacology·Dandan ChenJunbiao Wu
May 25, 2021·American Journal of Physiology. Renal Physiology·Liang NingJeffrey H Miner
Jun 19, 2021·Nature Reviews. Nephrology·Karl Tryggvason
Aug 31, 2021·Frontiers in Genetics·Liam ShawKevin J Hamill

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