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

Brent Wagner, Chunyan Tan, Jeffrey L. Barnes, Seema Ahuja, Thomas L. Davis, Yves Gorin, Fabio Jimenez

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1941-1952
Number of pages12
JournalAmerican Journal of Pathology
Volume181
Issue number6
DOIs
StatePublished - Dec 1 2012

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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