Nephrogenic systemic fibrosis is associated with
gadolinium contrast exposure in patients with reduced kidney function and carries high morbidity and mortality. We have previously demonstrated that
gadolinium contrast agents induce in vivo systemic
iron mobilization and in vitro differentiation of peripheral blood mononuclear cells into
ferroportin (
iron exporter)-expressing fibrocytic cells. In the present study we examined the role of
iron in a mouse model of
nephrogenic systemic fibrosis.
Chronic kidney disease was induced in 8-week-old male Balb/C mice with a two-step 5/6
nephrectomy surgery. Five groups of mice were studied: control (n = 5),
sham surgery control (n = 5),
chronic kidney disease control (n = 4),
chronic kidney disease injected with 0.5 mmol/kg
body weight of
Omniscan 3 days per week, for a total of 10
injections (n = 8), and
chronic kidney disease with
Omniscan plus
deferiprone, 125 mg/kg, in
drinking water (n = 9).
Deferiprone was continued for 16 weeks until the end of the experiment. Mice with
chronic kidney disease injected with
Omniscan developed skin changes characteristic of
nephrogenic systemic fibrosis including
hair loss, reddening, ulceration, and skin tightening by 10 to 16 weeks. Histopathological sections demonstrated dermal
fibrosis with increased skin thickness (0.25±0.06 mm,
sham; 0.34±+0.3 mm,
Omniscan-injected). Additionally, we observed an increase in tissue infiltration of
ferroportin-expressing, fibrocyte-like cells accompanied by tissue
iron accumulation in the skin of the
Omniscan-treated mice. The
deferiprone-treated group had significantly decreased skin thickness (p<0.05) and significantly decreased dermal
fibrosis compared to the
Omniscan-only group. In addition,
iron chelation prevented tissue infiltration of
ferroportin-expressing, fibrocyte-like cells. Our in vitro experiments demonstrated that exposure to
Omniscan resulted in the release of catalytic
iron and this was prevented by the
iron chelator deferiprone.
Deferiprone inhibited the differentiation of human peripheral blood mononuclear cells into
ferroportin-expressing cells by immunohistochemical staining and western blot analysis. Our studies support an important role of
iron in the pathophysiology of
gadolinium chelate toxicity and
nephrogenic systemic fibrosis.