Nephrogenic systemic fibrosis: evidence for oxidative stress and bone marrow-derived fibrocytes in skin, liver, and heart lesions using a 5/6 nephrectomy rodent model

Am J Pathol. 2012 Dec;181(6):1941-52. doi: 10.1016/j.ajpath.2012.08.026. Epub 2012 Oct 4.


Nephrogenic systemic fibrosis (NSF) is associated with gadolinium-based magnetic resonance imaging (MRI) contrast exposure in the setting of acute or chronic renal compromise. It has been proposed that circulating fibrocytes mediate the disease. A study was conducted to determine whether bone marrow-derived fibroblast precursors are involved in contributing to organ fibrosis in MRI contrast-treated rodents with renal insufficiency. Rats status post 5/6 nephrectomy underwent bone marrow transplant from human placental alkaline phosphatase (hPAP)-expressing donors. After engraftment, animals were treated with gadolinium-based MRI contrast (2.5 mmol/kg IP), during weekdays for 4 weeks, or an equivalent volume of normal saline. Dermal cellularity in the contrast-treated group was fourfold that of control. Skin cells from the contrast-treated group demonstrated greater hPAP expression with co-expression of pro-collagen I and α-smooth muscle actin-positive stress fibers. Donor and host cells expressed CD34. Dihydroethidium staining of skin was greater in the contrast-treated animals, indicating oxidative stress. This was abrogated when the animals were co-administered the superoxide dismutase mimetic tempol. In conclusion, a bone marrow-derived cell population is increased in the dermis of MRI contrast-treated rodents. The cell markers are consistent with fibrocytes mediating the disease. These changes correlate with oxidative stress and expression of Nox4, suggestive of a novel therapeutic target. Elucidation of the mechanisms of MRI contrast-induced fibrosis may aid in discovering therapies to this devastating disease.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, CD34 / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Bone Marrow / pathology*
  • Collagen Type I / metabolism
  • Contrast Media / adverse effects
  • Dermis / pathology
  • Disease Models, Animal
  • Extracellular Matrix / metabolism
  • Factor XIIIa / metabolism
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Fibrosis
  • Humans
  • Liver / metabolism
  • Liver / pathology*
  • Magnetic Resonance Imaging
  • Myocardium / pathology*
  • Nephrectomy
  • Nephrogenic Fibrosing Dermopathy / metabolism
  • Nephrogenic Fibrosing Dermopathy / pathology*
  • Organ Size
  • Oxidative Stress*
  • Rats
  • Rats, Inbred F344
  • Reactive Oxygen Species / metabolism
  • Skin / metabolism
  • Skin / pathology*
  • Skinfold Thickness


  • Antigens, CD
  • Antigens, CD34
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • Collagen Type I
  • Contrast Media
  • Reactive Oxygen Species
  • Factor XIIIa