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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

Deferiprone down-regulates Omniscan-induced procollagen-1+ cells in NSF skin as shown by immunohistochemistry.As indicated by arrows, Omniscan induced procollagen-1+ cells and accumulation of collagen bundles in the skin of CKD mice. Quantitative analysis of the number of positively stained cells is in μm2. (**p<0.01 Omniscan alone compared with control or Omniscan-treated compared with deferiprone and Omniscan).
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pone.0136563.g004: Deferiprone down-regulates Omniscan-induced procollagen-1+ cells in NSF skin as shown by immunohistochemistry.As indicated by arrows, Omniscan induced procollagen-1+ cells and accumulation of collagen bundles in the skin of CKD mice. Quantitative analysis of the number of positively stained cells is in μm2. (**p<0.01 Omniscan alone compared with control or Omniscan-treated compared with deferiprone and Omniscan).

Mentions: Deferiprone provided significant macroscopic protection against Omniscan-induced NSF including reduction in redness, loss of hair, ulceration, and skin tightening. A histopathological study confirmed the protective effects of deferiprone. In deferiprone-treated mice, subcutaneous adipose tissues were well preserved (Fig 2A). Quantitative measurements of skin biopsies showed a significant decrease (p<0.05) in thickness in Omniscan plus deferiprone-treated mice with CKD compared to the Omniscan-only treated group (Fig 2B). Markers CD163 and procollagen showed a marked reduction after deferiprone treatment as observed by immunohistochemistry staining (Figs 3A and 4A) and quantitative analysis (p<0.01) (Figs 3B and 4B). CD34 was not reduced significantly with deferiprone treatment (Fig 5B). The water consumption for each group was similar.


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)

Deferiprone down-regulates Omniscan-induced procollagen-1+ cells in NSF skin as shown by immunohistochemistry.As indicated by arrows, Omniscan induced procollagen-1+ cells and accumulation of collagen bundles in the skin of CKD mice. Quantitative analysis of the number of positively stained cells is in μm2. (**p<0.01 Omniscan alone compared with control or Omniscan-treated compared with deferiprone and Omniscan).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0136563.g004: Deferiprone down-regulates Omniscan-induced procollagen-1+ cells in NSF skin as shown by immunohistochemistry.As indicated by arrows, Omniscan induced procollagen-1+ cells and accumulation of collagen bundles in the skin of CKD mice. Quantitative analysis of the number of positively stained cells is in μm2. (**p<0.01 Omniscan alone compared with control or Omniscan-treated compared with deferiprone and Omniscan).
Mentions: Deferiprone provided significant macroscopic protection against Omniscan-induced NSF including reduction in redness, loss of hair, ulceration, and skin tightening. A histopathological study confirmed the protective effects of deferiprone. In deferiprone-treated mice, subcutaneous adipose tissues were well preserved (Fig 2A). Quantitative measurements of skin biopsies showed a significant decrease (p<0.05) in thickness in Omniscan plus deferiprone-treated mice with CKD compared to the Omniscan-only treated group (Fig 2B). Markers CD163 and procollagen showed a marked reduction after deferiprone treatment as observed by immunohistochemistry staining (Figs 3A and 4A) and quantitative analysis (p<0.01) (Figs 3B and 4B). CD34 was not reduced significantly with deferiprone treatment (Fig 5B). The water consumption for each group was similar.

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