Role of platelet-derived growth factor-CC in capillary rarefaction in renal fibrosis

Peter Boor, Janka Babickova, Floor Steegh, Petra Hautvast, Ina V. Martin, Sonja Djudjaj, Taizo Nakagawa, Josef Ehling, Felix Gremse, Eva Bücher, Ulf Eriksson, Claudia R.C. van Roeyen, Frank Eitner, Twan Lammers, Jürgen Floege, Carine J. Peutz-Kootstra, Tammo Ostendorf

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12 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2132-2142
JournalAmerican journal of pathology
Volume185
Issue number8
DOIs
Publication statusPublished - 2015

Keywords

  • IR-103938
  • METIS-321764

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    Boor, P., Babickova, J., Steegh, F., Hautvast, P., Martin, I. V., Djudjaj, S., ... Ostendorf, T. (2015). Role of platelet-derived growth factor-CC in capillary rarefaction in renal fibrosis. American journal of pathology, 185(8), 2132-2142. https://doi.org/10.1016/j.ajpath.2015.04.022