title: Neuropilin1 regulates glomerular function and basement membrane composition through pericytes in the mouse kidney.
abstract: Neuropilin1 (Nrp1) is a co-receptor best known to regulate the development of endothelial cells and is a target of anticancer therapies. However, its role in other vascular cells including pericytes is emergent. The kidney is an organ with high pericyte density and cancer patients develop severe proteinuria following administration of NRP1B-neutralizing antibody combined with bevacizumab. Therefore, we investigated whether Nrp1 regulates glomerular capillary integrity after completion of renal development using two mouse models; tamoxifen-inducible NG2Cre to delete Nrp1 specifically in pericytes and administration of Nrp1-neutralizing antibodies. Specific Nrp1 deletion in pericytes did not affect pericyte number but mutant mice developed hematuria with glomerular basement membrane defects. Despite foot process effacement, albuminuria was absent and expression of podocyte proteins remained unchanged upon Nrp1 deletion. Additionally, these mice displayed dilation of the afferent arteriole and glomerular capillaries leading to glomerular hyperfiltration. Nidogen-1 mRNA was downregulated and collagen4α3 mRNA was upregulated with no significant effect on the expression of other basement membrane genes in the mutant mice. These features were phenocopied by treating wild-type mice with Nrp1-neutralizing antibodies. Thus, our results reveal a postdevelopmental role of Nrp1 in renal pericytes as an important regulator of glomerular basement membrane integrity. Furthermore, our study offers novel mechanistic insights into renal side effects of Nrp1 targeting cancer therapies.
authors.affiliation: Institute of Anatomy, University of Bern, Bern, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Wnuk
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Anderegg
authors.affiliation: Institute of Anatomy, University of Bern, Bern, Switzerland.
authors.forename: Werner A
authors.initials: WA
authors.lastname: Graber
authors.affiliation: Institute of Anatomy, University of Bern, Bern, Switzerland.
authors.forename: Regula
authors.initials: R
authors.lastname: Buergy
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; Division of Nephrology, Hypertension, and Clinical Pharmacology, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Fuster
authors.affiliation: Institute of Anatomy, University of Bern, Bern, Switzerland. Electronic address: valentin.djonov@ana.unibe.ch.
authors.forename: Valentin
authors.initials: V
authors.lastname: Djonov
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D005919:Glomerular Filtration Rate; D006417:Hematuria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014664:Vasodilation
chemical_list: D057134:Antibodies, Neutralizing; D001324:Autoantigens; D024141:Collagen Type IV; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C029967:nidogen; C057112:type IV collagen alpha3 chain; D039942:Neuropilin-1
keywords: NRP1B; basement membrane; hyperfiltration; neuropilin1; pericyte