Identification of platelet-derived growth factor C as a mediator of both renal fibrosis and hypertension

Kidney Int. 2019 May;95(5):1103-1119. doi: 10.1016/j.kint.2018.11.031. Epub 2019 Feb 28.


Platelet-derived growth factors (PDGF) have been implicated in kidney disease progression. We previously found that PDGF-C is upregulated at sites of renal fibrosis and that antagonism of PDGF-C reduces fibrosis in the unilateral ureteral obstruction model. We studied the role of PDGF-C in collagen 4A3-/- ("Alport") mice, a model of progressive renal fibrosis with greater relevance to human kidney disease. Alport mice were crossbred with PDGF-C-/- mice or administered a neutralizing PDGF-C antibody. Both PDGF-C deficiency and neutralization reduced serum creatinine and blood urea nitrogen levels and mitigated glomerular injury, renal fibrosis, and renal inflammation. Unexpectedly, systolic blood pressure was also reduced in both Alport and wild-type mice treated with a neutralizing PDGF-C antibody. Neutralization of PDGF-C reduced arterial wall thickness in the renal cortex of Alport mice. Aortic rings isolated from anti-PDGF-C-treated wildtype mice exhibited reduced tension and faster relaxation than those of untreated mice. In vitro, PDGF-C upregulated angiotensinogen in aortic tissue and in primary hepatocytes and induced nuclear factor κB (NFκB)/p65-binding to the angiotensinogen promoter in hepatocytes. Neutralization of PDGF-C suppressed transcript expression of angiotensinogen in Alport mice and angiotensin II receptor type 1 in Alport and wildtype mice. Finally, administration of neutralizing PDGF-C antibodies ameliorated angiotensin II-induced hypertension in healthy mice. Thus, in addition to its key role in mediating renal fibrosis, we identified PDGF-C as a mediator of hypertension via effects on renal vasculature and on the renin-angiotensin system. The contribution to both renal fibrosis and hypertension render PDGF-C an attractive target in progressive kidney disease.

Keywords: PDGF-C; angiotensin; angiotensinogen; hypertension; renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensinogen / metabolism
  • Animals
  • Blood Pressure / genetics
  • Cells, Cultured
  • Collagen Type IV / genetics
  • Disease Models, Animal
  • Fibrosis
  • Hepatocytes
  • Humans
  • Hypertension / etiology
  • Hypertension / genetics
  • Hypertension / pathology*
  • Kidney / pathology*
  • Lymphokines / antagonists & inhibitors
  • Lymphokines / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Platelet-Derived Growth Factor / antagonists & inhibitors
  • Platelet-Derived Growth Factor / metabolism*
  • Primary Cell Culture
  • Up-Regulation
  • Ureter / surgery


  • Collagen Type IV
  • Lymphokines
  • Platelet-Derived Growth Factor
  • platelet-derived growth factor C
  • Angiotensinogen