title: Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells.
abstract: Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins with large extracellular domains that interact with class 3 semaphorins, vascular endothelial growth factor (VEGF) family members, and ligands, such as hepatocyte growth factor, platelet-derived growth factor BB, transforming growth factor-beta1 (TGF-beta1), and fibroblast growth factor2 (FGF2). Neuropilins (NRPs) have been implicated in tumor growth and vascularization, as novel mediators of the primary immune response and in regeneration and repair; however, their role in renal pathophysiology is largely unknown. Here, we report upregulation of tubular and interstitial NRP2 protein expression in patients with focal segmental glomerulosclerosis (FSGS). In an additional cohort of patients with minimal change disease (MCD), membranous nephropathy (MN), and FSGS, elevated NRP2 mRNA expression in kidney biopsies inversely correlated with estimated glomerular filtration rate (eGFR) at the time of biopsy. Furthermore, upregulation of NRP2 mRNA correlated with post-bioptic decline of kidney function. Expression of NRP1 and NRP2 in human proximal tubular cells (PTCs) was differentially affected after stimulation with TGF-beta1, interleukin-1beta (IL-1beta), and oncostatin M (OSM). Although the pro-fibrotic mediators, TGF-beta1 and IL-1beta, induced upregulation of NRP2 expression but downregulation of NRP1 expression, OSM stimulated the expression of both NRP1 and NRP2. Basal and OSM-induced NRP1 mRNA expression, as well as TGF-beta1-induced NRP2 mRNA and protein expression were partially mediated by MEK1/2-ERK1/2 signaling. This is the first report suggesting a differential role of NRP1 and NRP2 in renal fibrogenesis, and TGF-beta1, IL-1beta, and OSM represent the first ligands known to stimulate NRP2 expression in mammalian cells.
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. herbert.schramek@i-med.ac.at
authors.forename: Herbert
authors.initials: H
authors.lastname: Schramek
authors.forename: Rita
authors.initials: R
authors.lastname: Sarközi
authors.forename: Christina
authors.initials: C
authors.lastname: Lauterberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Kronbichler
authors.forename: Markus
authors.initials: M
authors.lastname: Pirklbauer
authors.forename: Rudolf
authors.initials: R
authors.lastname: Albrecht
authors.forename: Susie-Jane
authors.initials: SJ
authors.lastname: Noppert
authors.forename: Paul
authors.initials: P
authors.lastname: Perco
authors.forename: Michael
authors.initials: M
authors.lastname: Rudnicki
authors.forename: Frank M
authors.initials: FM
authors.lastname: Strutz
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D005919:Glomerular Filtration Rate; D015433:Glomerulonephritis, Membranous / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism*; D053683:Oncostatin M / Q000494:pharmacology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; D039943:Neuropilin-2; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D053683:Oncostatin M; D039942:Neuropilin-1