Supplemental Digital Content is available in the text. Renal fibrosis is the final pathological process common for several types of end-stage renal diseases, including obstructive nephropathy and diabetic kidney disease. Substantial renal iron loads and oxidative stress have been reported to contribute to the development of renal diseases. TfR1 (transferrin receptor 1) plays a crucial role in cellular iron transport. However, there are no studies investigating TfR1 in the pathophysiology of renal fibrosis. Here, we investigate the role of TfR1 in the development of renal fibrosis. Primarily, to ascertain an association of TfR1 in the pathophysiology of renal fibrosis, we induced unilateral ureteral obstruction in wild-type (WT) and heterozygous TfR1 deleted (TfR1+/−) mice. TfR1+/− mice exhibited attenuated renal fibrosis, along with reduced renal expression of ferritin and 4-hydroxynonenal as compared with WT mice after unilateral ureteral obstruction. In addition, renal expression of TGFβ-RI (transforming growth factor-β receptor I) and Smad2, downstream signaling of TGFβ-RI was attenuated in TfR1+/− mice compared with WT mice after unilateral ureteral obstruction. Next, we investigated the role of TfR1 in the development of diabetic kidney disease. No difference was observed in blood glucose levels and urinary albumin:creatinine ratios between WT and TfR1+/− diabetic mice after streptozotocin administration. In contrast, TfR1+/− mice showed suppressed renal fibrosis, along with reduced renal expression of ferritin, 4-hydroxynonenal, TGFβ-RI, and Smad2 compared with WT mice after streptozotocin administration. These results suggest that TfR1 plays an important role in the development of renal fibrosis.

中文翻译：

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杂合 TfR1（转铁蛋白受体 1）缺失对小鼠肾纤维化发病机制的影响

补充数字内容在文本中可用。肾纤维化是几种终末期肾病常见的最终病理过程，包括阻塞性肾病和糖尿病肾病。据报道，大量的肾脏铁负荷和氧化应激有助于肾脏疾病的发展。TfR1（转铁蛋白受体 1）在细胞铁转运中起关键作用。然而，没有研究调查 TfR1 在肾纤维化病理生理学中的作用。在这里，我们研究了 TfR1 在肾纤维化发展中的作用。首先，为了确定 TfR1 在肾纤维化病理生理学中的关联，我们在野生型 (WT) 和杂合的 TfR1 缺失 (TfR1+/-) 小鼠中诱导了单侧输尿管梗阻。TfR1+/- 小鼠表现出减轻的肾纤维化，与单侧输尿管梗阻后的 WT 小鼠相比，铁蛋白和 4-羟基壬烯醛的肾脏表达降低。此外，与单侧输尿管梗阻后的 WT 小鼠相比，TGFβ-RI（转化生长因子-β 受体 I）和 Smad2 的肾脏表达，TfR1+/- 小鼠中 TGFβ-RI 的下游信号传导减弱。接下来，我们研究了 TfR1 在糖尿病肾病发展中的作用。在链脲佐菌素给药后，WT 和 TfR1+/- 糖尿病小鼠之间的血糖水平和尿白蛋白：肌酐比率没有差异。相比之下，与链脲佐菌素给药后的 WT 小鼠相比，TfR1 +/- 小鼠的肾纤维化受到抑制，同时铁蛋白、4-羟基壬烯醛、TGFβ-RI 和 Smad2 的肾表达降低。