Glucose induced regulation of iron transporters implicates kidney iron accumulation

IF 2.8 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Rajiv Kumar , Diksha Kulshreshtha , Ayushi Aggarwal , Somya Asthana , Amit Dinda , Chinmay K. Mukhopadhyay
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Abstract

Increased iron level is detected in rat kidney and human urine in diabetic condition and implicated in associated nephropathy. However, the biological cue and mechanism of the iron accumulation remain unclear. Here we reveal that glucose increases iron uptake by promoting transferrin receptor 1 (TFRC) in kidney cells by a translational mechanism but does not alter expression of endosomal iron transporter DMT1. Glucose decreases iron exporter ferroportin (FPN) by a protein degradation mechanism. Hepcidin is known to bind at Cys-326 residue in promoting degradation of human ferroportin. When Cys-326 was mutated to Ser in human-FPN-FLAG and expressed in kidney cells, glucose still could degrade FPN-FLAG implicating involvement of hepcidin independent mechanism in glucose induced ferroportin degradation. Chronic hyperglycemia was generated in rats by administering streptozotocin (STZ) with periodic insulin injection to determine the level of iron homeostasis components. Increased TFRC and decreased ferroportin levels were detected in hyperglycemic rat kidney by Western blot and immunohistochemistry analyses. Hepcidin mRNA was not significantly altered in kidney but was marginally decreased in liver. Perls' staining and non-heme iron estimation showed an elevated iron level in hyperglycemic rat kidney. These results suggest that high glucose dysregulates iron transport components resulting iron accumulation in diabetic kidney.

葡萄糖诱导铁转运体的调节与肾脏铁积累有关
在糖尿病患者的大鼠肾脏和人体尿液中检测到铁含量增加,这与相关的肾病有关。然而,铁积累的生物学线索和机制仍不清楚。在这里,我们发现葡萄糖通过翻译机制促进肾脏细胞中的转铁蛋白受体1(TFRC),从而增加铁的吸收,但并不改变内体铁转运体DMT1的表达。葡萄糖通过蛋白质降解机制减少铁输出蛋白铁蛋白(FPN)。已知肝素能与 Cys-326 残基结合,促进人铁蛋白的降解。当人-FPN-FLAG 中的 Cys-326 突变为 Ser 并在肾细胞中表达时,葡萄糖仍能降解 FPN-FLAG,这表明葡萄糖诱导铁转运蛋白降解的机制与肝素无关。通过给大鼠注射链脲佐菌素(STZ)并定期注射胰岛素来产生慢性高血糖,以测定铁稳态成分的水平。通过 Western 印迹和免疫组化分析,检测到高血糖大鼠肾脏中 TFRC 水平升高,铁蛋白水平降低。肾脏中的肝素 mRNA 没有明显变化,但肝脏中的肝素 mRNA 略有下降。Perls 染色和非血红素铁估算显示,高血糖大鼠肾脏中的铁含量升高。这些结果表明,高血糖使铁转运成分失调,从而导致糖尿病肾脏中铁的积累。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biochimica et biophysica acta. General subjects
Biochimica et biophysica acta. General subjects 生物-生化与分子生物学
CiteScore
6.40
自引率
0.00%
发文量
139
审稿时长
30 days
期刊介绍: BBA General Subjects accepts for submission either original, hypothesis-driven studies or reviews covering subjects in biochemistry and biophysics that are considered to have general interest for a wide audience. Manuscripts with interdisciplinary approaches are especially encouraged.
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