Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
PLoS One. 2013 Sep 9;8(9):e73655. doi: 10.1371/journal.pone.0073655. eCollection 2013.
To determine whether delayed administration of a single dose of suramin, a drug that has been used extensively in humans to treat trypanosomiasis, attenuates renal injury in a leptin receptor deficient C57BLKS/J db/db type 2 diabetic nephropathy (T2DN) mouse model.
Groups of female non-diabetic (control) db/m and diabetic db/db mice of 8 and 16 weeks of age, respectively, were treated with suramin (10 mg/kg) or saline i.v. All animals were euthanized one week later. Measurements in mice 1 week following treatment included the following: body weight; blood glucose; urinary protein excretion; pathological lesions in glomeruli and proximal tubules; changes in protein expression of pro-inflammatory transcription factor nuclear factor κB (NF-κB) and intracellular adhesion molecule-1 (ICAM-1), profibrotic transforming growth factor-β1 (TGF-β1), phospho-SMAD-3 and alpha-smooth muscle actin (α-SMA); and immunohistochemical analysis of leukocyte infiltration and collagen 1A2 (COL1A2) deposition.
Immunoblot analysis revealed increased NF-κB, ICAM-1, TGF-β1, phospho-SMAD-3, and α-SMA proteins in both 9 and 17 week db/db mice as compared to db/m control mice. Immunohistochemical analysis revealed moderate leukocyte infiltration and collagen 1A2 (COL1A2) deposition in 9 week db/db mice that was increased in the 17 week db/db mice. Importantly, suramin significantly decreased expression of all these markers in 9 week db/db mice and partially decreased in 17 week db/db mice without altering body weight, blood glucose or urinary protein excretion. There was no difference in creatinine clearance between 9 week db/m and db/db mice ± suramin. Importantly, in the 17 week db/db mice suramin intervention reversed the impaired creatinine clearance and overt histological damage.
Delayed administration of a single dose of suramin in a model of T2DN attenuated inflammation and fibrosis as well as improved renal function, supporting the use of suramin in T2DN.
确定延迟给予单次剂量苏拉明（一种广泛用于治疗锥虫病的药物）是否可以减轻 2 型糖尿病肾病（T2DN）C57BLKS/J db/db 瘦素受体缺陷型小鼠模型中的肾脏损伤。
分别给 8 周龄和 16 周龄的雌性非糖尿病（对照）db/m 和糖尿病 db/db 小鼠静脉注射苏拉明（10mg/kg）或生理盐水。所有动物在一周后处死。治疗后一周，对小鼠进行以下测量：体重；血糖；尿蛋白排泄量；肾小球和近端肾小管的病理损伤；促炎转录因子核因子 κB（NF-κB）和细胞间黏附分子-1（ICAM-1）、致纤维化转化生长因子-β1（TGF-β1）、磷酸化 SMAD-3 和α-平滑肌肌动蛋白（α-SMA）的蛋白表达变化；白细胞浸润和胶原 1A2（COL1A2）沉积的免疫组化分析。
免疫印迹分析显示，与 db/m 对照小鼠相比，9 周和 17 周 db/db 小鼠的 NF-κB、ICAM-1、TGF-β1、磷酸化 SMAD-3 和α-SMA 蛋白表达增加。免疫组化分析显示，9 周 db/db 小鼠有中等程度的白细胞浸润和胶原 1A2（COL1A2）沉积，17 周 db/db 小鼠则更严重。重要的是，苏拉明显著降低了 9 周 db/db 小鼠的所有这些标志物的表达，部分降低了 17 周 db/db 小鼠的表达，而不改变体重、血糖或尿蛋白排泄。9 周 db/m 和 db/db 小鼠加或不加苏拉明的肌酐清除率无差异。重要的是，在 17 周 db/db 小鼠中，苏拉明干预逆转了受损的肌酐清除率和明显的组织学损伤。
在 T2DN 模型中延迟给予单次剂量苏拉明可减轻炎症和纤维化，改善肾功能，支持苏拉明在 T2DN 中的应用。
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