Neuropilin1 regulates glomerular function and basement membrane composition through pericytes in the mouse kidney.

Wnuk, Monika; Anderegg, Manuel; Graber, Werner Adrian; Buergy, Regula; Fuster, Daniel Guido; Djonov, Valentin (2017). Neuropilin1 regulates glomerular function and basement membrane composition through pericytes in the mouse kidney. Kidney international, 91(4), pp. 868-879. Elsevier 10.1016/j.kint.2016.10.010

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Topographical and Clinical Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie

UniBE Contributor:

Wnuk, Monika; Anderegg, Manuel; Graber, Werner Adrian; Buergy, Regula; Fuster, Daniel Guido and Djonov, Valentin

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1523-1755

Publisher:

Elsevier

Language:

English

Submitter:

David Christian Haberthür

Date Deposited:

28 Dec 2016 10:23

Last Modified:

19 Mar 2017 01:30

Publisher DOI:

10.1016/j.kint.2016.10.010

PubMed ID:

27988210

Uncontrolled Keywords:

NRP1B; basement membrane; hyperfiltration; neuropilin1; pericyte

URI:

https://boris.unibe.ch/id/eprint/91725

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