title: Role of platelet-derived growth factor-CC in capillary rarefaction in renal fibrosis.
abstract: We have identified platelet-derived growth factor (PDGF)-CC as a potent profibrotic mediator in kidney fibrosis and pro-angiogenic mediator in glomeruli. Because renal fibrosis is associated with progressive capillary rarefaction, we asked whether PDGF-CC neutralization in fibrosis might have detrimental anti-angiogenic effects leading to aggravated peritubular capillary loss. We analyzed capillary rarefaction in mice with and without PDGF-CC neutralization (using genetically deficient mice and neutralizing antibodies), in three different models of renal interstitial fibrosis, unilateral ureteral obstruction, unilateral ischemia-reperfusion, Col4a3-deficient (Alport) mice, and healthy animals. Independent of the effect of PDGF-CC neutralization on renal fibrosis, we found no difference in capillary rarefaction between PDGF-CC-neutralized mice and mice with intact PDGF-CC. We also found no differences in microvascular leakage (determined by extravasation of Evans Blue Dye) and in renal relative blood volume quantified using in vivo microcomputed tomography. PDGF-CC neutralization had no effects on renal microvasculature in healthy animals. Capillary endothelium did not express PDGF receptor-α, suggesting that potential PDGF-CC effects would have to be indirect. PDGF-CC neutralization or deficiency was not associated with preservation or accelerated loss of peritubular capillaries, suggesting no significant pro-angiogenic effects of PDGF-CC during renal fibrosis. From a clinical perspective, the profibrotic effects of PDGF-CC outweigh the pro-angiogenic effects and, thus, do not limit a potential therapeutic use of PDGF-CC inhibition in renal fibrosis.
authors.affiliation: Institute of Pathology, RWTH Aachen University, Aachen, Germany; Division of Nephrology, RWTH Aachen University, Aachen, Germany; Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia. Electronic address: pboor@ukaachen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.affiliation: Division of Nephrology, RWTH Aachen University, Aachen, Germany; Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia; Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Janka
authors.initials: J
authors.lastname: Bábíčková
authors.affiliation: Institute of Pathology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Floor
authors.initials: F
authors.lastname: Steegh
authors.affiliation: Institute of Pathology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Hautvast
authors.affiliation: Division of Nephrology, RWTH Aachen University, Aachen, Germany.
authors.forename: Ina V
authors.initials: IV
authors.lastname: Martin
authors.affiliation: Institute of Pathology, RWTH Aachen University, Aachen, Germany; Division of Nephrology, RWTH Aachen University, Aachen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Djudjaj
authors.affiliation: Division of Nephrology, RWTH Aachen University, Aachen, Germany.
authors.forename: Taizo
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Ehling
authors.affiliation: Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Gremse
authors.affiliation: Division of Nephrology, RWTH Aachen University, Aachen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Bücher
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
authors.affiliation: Division of Nephrology, RWTH Aachen University, Aachen, Germany.
authors.forename: Claudia R C
authors.initials: CR
authors.lastname: van Roeyen
authors.affiliation: Bayer Healthcare, Wuppertal, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.affiliation: Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.affiliation: Division of Nephrology, RWTH Aachen University, Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.affiliation: Institute of Pathology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Carine J
authors.initials: CJ
authors.lastname: Peutz-Kootstra
authors.affiliation: Division of Nephrology, RWTH Aachen University, Aachen, Germany.
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
mesh_terms: D000818:Animals; D002196:Capillaries / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C