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Evidence Suggesting a Role of Iron in a Mouse Model of Nephrogenic Systemic Fibrosis.

Bose C, Megyesi JK, Shah SV, Hiatt KM, Hall KA, Karaduta O, Swaminathan S - PLoS ONE (2015)

Bottom Line: The deferiprone-treated group had significantly decreased skin thickness (p<0.05) and significantly decreased dermal fibrosis compared to the Omniscan-only group.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.Our studies support an important role of iron in the pathophysiology of gadolinium chelate toxicity and nephrogenic systemic fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Central Arkansas Veterans Healthcare System, Renal Section, Medicine Service, Little Rock, Arkansas, United States of America; University of Arkansas for Medical Sciences, Department of Internal Medicine, Division of Nephrology, Little Rock, Arkansas, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Expression of hepcidin in Omniscan-injected CKD mice.Hepcidin was slightly down-regulated after Omniscan treatment. Pretreatment with deferiprone partially increased hepcidin expression.
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pone.0136563.g011: Expression of hepcidin in Omniscan-injected CKD mice.Hepcidin was slightly down-regulated after Omniscan treatment. Pretreatment with deferiprone partially increased hepcidin expression.

Mentions: We further examined cellular localization and expression of ferroportin and hepcidin in the skin biopsies. As shown in Fig 10A, many fibrocyte-like spindle-shaped cells in the dermis of Omniscan-treated mice strongly expressed ferroportin, and hepcidin expression was lower than in sham-operated mice (Fig 11A). In mice that received deferiprone along with Omniscan, there was a marked reduction in the number of ferroportin-expressing fibrocyte-like cells accompanied by slight increased dermal hepcidin expression (Figs 10A and 11A). Quantitative analysis demonstrated that the number of cells positive for ferroportin were significantly (p<0.001) increased after Omniscan injections, whereas deferiprone treatment markedly (p<0.001) reduced ferroportin-expressing cells (Fig 10B). The number of hepcidin-expressing cells in sham and deferiprone-treated groups, and Omniscan-injected CKD mice, were not statistically significant (Fig 11B).


Evidence Suggesting a Role of Iron in a Mouse Model of Nephrogenic Systemic Fibrosis.

Bose C, Megyesi JK, Shah SV, Hiatt KM, Hall KA, Karaduta O, Swaminathan S - PLoS ONE (2015)

Expression of hepcidin in Omniscan-injected CKD mice.Hepcidin was slightly down-regulated after Omniscan treatment. Pretreatment with deferiprone partially increased hepcidin expression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549214&req=5

pone.0136563.g011: Expression of hepcidin in Omniscan-injected CKD mice.Hepcidin was slightly down-regulated after Omniscan treatment. Pretreatment with deferiprone partially increased hepcidin expression.
Mentions: We further examined cellular localization and expression of ferroportin and hepcidin in the skin biopsies. As shown in Fig 10A, many fibrocyte-like spindle-shaped cells in the dermis of Omniscan-treated mice strongly expressed ferroportin, and hepcidin expression was lower than in sham-operated mice (Fig 11A). In mice that received deferiprone along with Omniscan, there was a marked reduction in the number of ferroportin-expressing fibrocyte-like cells accompanied by slight increased dermal hepcidin expression (Figs 10A and 11A). Quantitative analysis demonstrated that the number of cells positive for ferroportin were significantly (p<0.001) increased after Omniscan injections, whereas deferiprone treatment markedly (p<0.001) reduced ferroportin-expressing cells (Fig 10B). The number of hepcidin-expressing cells in sham and deferiprone-treated groups, and Omniscan-injected CKD mice, were not statistically significant (Fig 11B).

Bottom Line: The deferiprone-treated group had significantly decreased skin thickness (p<0.05) and significantly decreased dermal fibrosis compared to the Omniscan-only group.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.Our studies support an important role of iron in the pathophysiology of gadolinium chelate toxicity and nephrogenic systemic fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Central Arkansas Veterans Healthcare System, Renal Section, Medicine Service, Little Rock, Arkansas, United States of America; University of Arkansas for Medical Sciences, Department of Internal Medicine, Division of Nephrology, Little Rock, Arkansas, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus