Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease
Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease
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DOI：
10.1097/hjh.0b013e3283581a64
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发表时间：
2012-11-01
影响因子：
4.9
通讯作者：
Masuyama, Tohru
中科院分区：
文献类型：
--
作者：
Naito, Yoshiro;Fujii, Aya;Masuyama, Tohru
目的：铁与慢性肾脏病（CKD）的发病机制有关。盐皮质激素受体信号传导的激活与 CKD 相关；然而，CKD 中铁和盐皮质激素受体信号传导之间的联系仍不清楚。我们之前已经表明，长期饮食铁限制会导致大鼠尿液中钠的排泄增加和钾的排泄减少。在此，我们在 CKD 大鼠模型中研究了铁限制对肾损伤和盐皮质激素受体信号传导的影响。方法：通过 Sprague-Dawley 大鼠的 5/6 肾切除术诱导 CKD。 CKD大鼠分为未治疗组和饮食限铁组。结果：CKD大鼠出现蛋白尿、肾小球硬化、肾小管间质损伤和足细胞损伤。相比之下，这些变化因 16 周的铁限制饮食而减弱。与这些发现一致的是，铁限制抑制了 CKD 肾脏中 III 型胶原、转化生长因子-β、CD68 和肿瘤坏死因子-α 基因表达的增加。重要的是，CKD 肾脏中核盐皮质激素受体和 SGK1（盐皮质激素受体信号转导的关键下游效应器）表达的增加因铁限制而显着减弱。有趣的是，CKD 肾小管中细胞铁转运蛋白、转铁蛋白受体 1 和二价金属转运蛋白 1 的表达增加，同时铁积累、超氧化物产生和尿铁排泄增加。 CKD 大鼠也出现高血压，尽管铁限制抑制了高血压的发展。结论：总之，这些数据揭示了铁限制通过抑制肾脏盐皮质激素受体信号传导对肾损伤和高血压的新作用。
Objective: Iron is associated with the pathogenesis of chronic kidney disease (CKD). Activation of mineralocorticoid receptor signaling is implicated in CKD; however, a link between iron and mineralocorticoid receptor signaling in CKD remains unknown. We have previously shown that long-term dietary iron restriction leads to increased sodium and decreased potassium excretions in the rat urine. Herein, we investigated the effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of CKD.Methods: CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. CKD rats were divided into untreated and dietary iron-restricted groups.Results: CKD rats exhibited proteinuria, glomerulosclerosis, tubulointerstitinal damage, and podocyte injury. In contrast, these changes were attenuated by 16 weeks of iron-restricted diet. Consistent with these findings, iron restriction suppressed increased gene expression of collagen type III, transforming growth factor-beta, CD68, and tumor necrosis factor-alpha in the CKD kidney. Importantly, increased expression of nuclear mineralocorticoid receptor and SGK1, a key downstream effector of mineralocorticoid receptor signaling, in the CKD kidney was markedly attenuated by iron restriction. Of interest, expression of cellular iron transport proteins, transferrin receptor 1, and divalent metal transporter 1 was increased in the CKD renal tubules, along with increased iron accumulation, superoxide production, and urinary iron excretion. CKD rats also developed hypertension, although iron restriction suppressed the development of hypertension.Conclusion: Taken together, these data uncover a novel effect of iron restriction on renal damage and hypertension through the inhibition of renal mineralocorticoid receptor signaling.