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: Peter Boor, Janka Bábíčková, 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
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 8 Pg. 2132-42 (Aug 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 26216283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Lymphokines
• Platelet-Derived Growth Factor
• platelet-derived growth factor C

Topics

• Animals
• Capillaries (metabolism, pathology)
• Disease Models, Animal
• Fibrosis (metabolism, pathology)
• Kidney (metabolism, pathology)
• Kidney Diseases (metabolism, pathology)
• Kidney Glomerulus (metabolism, pathology)
• Lymphokines (genetics, metabolism)
• Mice
• Mice, Knockout
• Platelet-Derived Growth Factor (genetics, metabolism)
• Ureteral Obstruction (metabolism, pathology)