title: The role of PDGF-D in healthy and fibrotic kidneys.
abstract: Platelet-derived growth factor (PDGF)-D, a specific PDGF receptor β (PDGFR-β) ligand, mediates mesangial proliferation in vitro and in vivo. However, its role in renal development, physiology, and fibrosis is relatively unknown. In healthy murine kidneys, PDGF-D was found to be expressed on renal mesenchymal cells (mesangial cells, fibroblasts, and vascular smooth muscle cells). During renal fibrosis, PDGF-D and its receptor PDGFR-β were markedly and similarly upregulated in both human and murine kidneys on activated mesenchymal cells, but PDGF-D was also expressed de novo in injured renal tubular cells. The functional role of PDGF-D was studied in Pdgfd-/- mice, which showed no obvious spontaneous renal phenotype at a young age or during aging. Compared with wild-type littermates, Pdgfd-/- mice had significantly reduced renal interstitial fibrosis in two models of renal scarring: unilateral ureteral obstruction and unilateral ischemia/reperfusion injury. This was associated with reduced phosphorylation of PDGFR-β and its downstream mediator p38. Systemic adenoviral overexpression of PDGF-D in healthy mice resulted in increased collagen deposition in the kidney interstitium. Thus, PDGF-D is upregulated in murine and human kidney fibrosis, may mediate renal scarring, and is dispensable for normal kidney development and physiological functions. PDGF-D may be a suitable therapeutic target to combat kidney fibrosis.
authors.affiliation: Division of Nephrology, RWTH University of Aachen, Aachen, Germany; Institute of Pathology, RWTH University of Aachen, Aachen, Germany.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Buhl
authors.affiliation: Institute of Pathology, RWTH University of Aachen, Aachen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Djudjaj
authors.affiliation: Division of Nephrology, RWTH University of Aachen, Aachen, Germany; Institute of Pathology, RWTH University of Aachen, Aachen, Germany; Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia.
authors.forename: Janka
authors.initials: J
authors.lastname: Babickova
authors.affiliation: Institute of Pathology, RWTH University of Aachen, Aachen, Germany.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Klinkhammer
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Folestad
authors.affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University of Aachen, Aachen, Germany.
authors.forename: Erawan
authors.initials: E
authors.lastname: Borkham-Kamphorst
authors.affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University of Aachen, Aachen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hudkins
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
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 University of Aachen, Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.affiliation: Division of Nephrology, RWTH University of Aachen, Aachen, Germany; Institute of Pathology, RWTH University of Aachen, Aachen, Germany; Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia. Electronic address: pboor@ukaachen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
mesh_terms: D000818:Animals; D006801:Humans; D007668:Kidney / Q000254:growth & development; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009400:Nephrosclerosis / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D008222:Lymphokines; C427493:PDGFD protein, human; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor
keywords: extracellular matrix; fibroblast; fibrosis; myofibroblast; platelet-derived growth factor