The Role of PDGF-D in Healthy and Fibrotic Kidneys

Kidney Int. 2016 Apr;89(4):848-61. doi: 10.1016/j.kint.2015.12.037. Epub 2016 Feb 18.

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.

Keywords: extracellular matrix; fibroblast; fibrosis; myofibroblast; platelet-derived growth factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Kidney / growth & development
  • Lymphokines / metabolism*
  • Male
  • Mice, Knockout
  • Nephrosclerosis / metabolism*
  • Platelet-Derived Growth Factor / metabolism*
  • Retrospective Studies

Substances

  • Lymphokines
  • PDGFD protein, human
  • Pdgfd protein, mouse
  • Platelet-Derived Growth Factor