Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease

Naito, Yoshiro; Fujii, Aya; Sawada, Hisashi; Hirotani, Shinichi; Iwasaku, Toshihiro; Eguchi, Akiyo; Ohyanagi, Mitsumasa; Tsujino, Takeshi; Masuyama, Tohru

doi:10.1097/hjh.0b013e3283581a64

Cited by 34 publications

(45 citation statements)

References 25 publications

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“…The transcriptional expression of SGK-1 has been previously reported to be downregulated by iron restriction in rat intestine (Marzullo et al 2004) and kidney of chronic kidney disease in a rat model (Naito et al 2012). Here, we consistently observed that iron restriction by the iron cheater BP represses the expression of SGK-1::GFP (MQD862, N2;Psgk1::sgk-1::gfp) in C. elegans ( Figure S5).…”

Section: Discussionsupporting

confidence: 79%

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Wang¹,

Jiang

et al. 2016

Genetics

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The trace element iron is crucial for living organisms, since it plays essential roles in numerous cellular functions. Systemic iron overload and the elevated level of ferritin, a ubiquitous intracellular protein that stores and releases iron to maintain the iron homeostasis in cells, has long been epidemiologically associated with obesity and obesity-related diseases. However, the underlying mechanisms of this association remain unclear. Here, using Caenorhabditis elegans, we show that iron overload induces the expression of sgk-1, encoding the serum and glucocorticoid-inducible kinase, to promote the level of ferritin and fat accumulation. Mutation of cyp-23A1, encoding a homolog of human cytochrome P450 CYP7B1 that is related to neonatal hemochromatosis, further enhances the elevated expression of ftn-1, sgk-1, and fat accumulation. sgk-1 positively regulates the expression of acs-20 and vit-2, genes encoding homologs of the mammalian FATP1/4 fatty acid transport proteins and yolk lipoproteins, respectively, to facilitate lipid uptake and translocation for storage under iron overload. This study reveals a completely novel pathway in which sgk-1 plays a central role to synergistically regulate iron and lipid homeostasis, offering not only experimental evidence supporting a previously unverified link between iron and obesity, but also novel insights into the pathogenesis of iron and obesity-related human metabolic diseases. KEYWORDS iron; serum and glucocorticoid inducible kinase SGK-1; lipid uptake; obesity; C. elegans D UE to its essential roles in numerous cellular functions across nearly all living organisms, including oxygen transport, electron transport, DNA synthesis, and enzyme catalysis, exploring how iron is stored and regulated has been a growing focus in numerous fields. Dietary iron is absorbed primarily by duodenal enterocytes via the divalent metal-ion transporter 1 (DMT1) after it is reduced at the apical membrane. Subsequently, it is either stored in ferritin, which dynamically regulates iron sequestration, storage, and release or it is transported from enterocytes into the blood stream via the basolateral transporter ferroportin (Fleming and Ponka 2012). Consequently, the total amount of iron in the body is determined by its intake and storage, which are all finely regulated by many factors and signaling pathways at various levels (Fleming and Ponka 2012;Hubler et al. 2015), many of which not entirely understood.Human epidemiology studies revealed that elevated levels of ferritin may be an indication of systemic iron overload (Cook et al. 1974;Zimmermann 2008) and are positively associated with obesity (Wenzel et al. 1962;Gillum 2001;Iwasaki et al. 2005) and obesity-related diseases such as diabetes, hypertension, dyslipidaemia, or nonalcoholic fatty liver disease (Jehn et al. 2004;Bozzini et al. 2005;Mascitelli et al. 2009;Dongiovanni et al. 2011;Kim et al. 2011; see Zafon et al. 2010 for review). Precisely why elevations in ferritin levels or systemic iron overload are associated w...

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Section: Discussionsupporting

confidence: 79%

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Wang¹,

Jiang

et al. 2016

Genetics

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“…We have previously demonstrated that iron is involved in the pathophysiology of hypertension and chronic kidney disease. 6,9,22,23 Moreover, these reports have shown that dietary IR attenuates the progression of cardiovascular remodeling and oxidative stress. We, therefore, hypothesized that iron is also involved in the pathophysiology of AAA and dietary IR could inhibit AAA formation via suppression of oxidative stress.…”

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confidence: 99%

Aortic Iron Overload With Oxidative Stress and Inflammation in Human and Murine Abdominal Aortic Aneurysm

Sawada

Hao

Naito

et al. 2015

ATVB

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A bdominal aortic aneurysm (AAA) is a common vascular disease, which occurs in ≈4% to 8% of men aged 65 to 80 years.1 Aortic rupture is the most feared clinical consequence of AAA progression, resulting in mortality in ≈90% of cases. [2][3][4] Because AAA usually progresses without symptoms, AAA is often discovered in advanced stage. At present, surgical aortic replacement and endovascular stent graft repair are performed as standard definitive therapies for AAA. However, there is no effective medical therapy to prevent aortic rupture in AAA. Although several studies have reported the pathophysiology of AAA, the mechanisms of AAA formation are largely unknown. Therefore, it is necessary to investigate the molecular pathophysiology of AAA to find noninvasive strategies for the prevention of AAA.Iron is an essential element for maintaining physiological function. However, excess iron causes tissue damage by oxidative stress via the Fenton/Haber-Weiss reaction. 5Therefore, iron is involved in the pathophysiology of several diseases including cardiovascular diseases. In fact, we have previously shown that iron accumulation and superoxide production are observed in the renal tubules of a rat model of chronic kidney disease.6 Lee et al 7 have shown that iron accumulation is observed in the atherosclerotic lesions of apolipoprotein E knockout mice. Most recently, Martinez-Pinna et al 8 have demonstrated that iron is deposited in human AAA walls. Meanwhile, we have also reported that dietary iron restriction (IR) prevents the development of hypertension and proteinuria with inhibition of oxidative stress and inflammation in Dahl salt-sensitive hypertensive rats.9 Although oxidative stress and inflammation are well known to be involved in the development of AAA formation, it has not been investigated whether iron is associated with the pathophysiology of AAA through © 2015 American Heart Association, Inc. Objective-Although iron is an essential element for maintaining physiological function, excess iron leads to tissue damage caused by oxidative stress and inflammation. Oxidative stress and inflammation play critical roles for the development of abdominal aortic aneurysm (AAA). However, it has not been investigated whether iron plays a role in AAA formation through oxidative stress and inflammation. We, therefore, examined whether iron is involved in the pathophysiology of AAA formation using human AAA walls and murine AAA models. Approach and Results-Human aortic walls were collected from 53 patients who underwent cardiovascular surgery (non-AAA=34; AAA=19). Murine AAA was induced by infusion of angiotensin II to apolipoprotein E knockout mice. Iron was accumulated in human and murine AAA walls compared with non-AAA walls. Immunohistochemistry showed that both 8-hydroxy-2′-deoxyguanosine and CD68-positive areas were increased in AAA walls compared with non-AAA walls. The extent of iron accumulated area positively correlated with that of 8-hydroxy-2′-deoxyguanosine expression area and macrophage infiltration area in huma...

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“…8 Also, we have previously shown that iron accumulation and TfR1 expression are increased in the renal tubules of rats with CKD. 9 Generally, iron is transported into cells through TfR1. TfR1 expression is normally upregulated under low-iron conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Of interest, we have previously reported that dietary iron restriction prevents the development of hypertension and proteinuria in rats with CKD. 9 In that study, renal mineralocorticoid receptor (MR) expression in the nuclear fraction was increased in CKD rats as compared with the controls, whereas circulating aldosterone levels were decreased in CKD rats compared with the controls. In general, it is widely accepted that exogenous high aldosterone and salt induce renal injury.…”

Section: Introductionmentioning

confidence: 90%

“…7,8 Furthermore, we have recently shown that renal iron accumulation and superoxide production are observed in a chronic kidney disease (CKD) model in rats. 9 Thus, iron is considered to be involved in the pathophysiology of several cardiovascular and renal diseases. Of interest, we have previously reported that dietary iron restriction prevents the development of hypertension and proteinuria in rats with CKD.…”

Section: Introductionmentioning

confidence: 99%

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Iron restriction inhibits renal injury in aldosterone/salt-induced hypertensive mice

et al. 2015

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Excess iron is associated with the pathogenesis of several renal diseases. Aldosterone is reported to have deleterious effects on the kidney, but there have been no reports of the role of iron in aldosterone/salt-induced renal injury. Therefore, we investigated the effects of dietary iron restriction on the development of hypertension and renal injury in aldosterone/salt-induced hypertensive mice. Ten-week-old male C57BL/6J mice were uninephrectomized and infused with aldosterone for four weeks. These were divided into two groups: one fed a high-salt diet (Aldo) and the other fed a high-salt with iron-restricted diet (Aldo-IR). Vehicle-infused mice without a uninephrectomy were also divided into two groups: one fed a normal diet (control) and the other fed an iron-restricted diet (IR) for 4 weeks. As compared with control and IR mice, Aldo mice showed an increase in both systolic blood pressure and urinary albumin/creatinine ratio, but these increases were reduced in the Aldo-IR group. In addition, renal histology revealed that Aldo mice exhibited glomerulosclerosis and tubulointerstitial fibrosis, whereas these changes were attenuated in Aldo-IR mice. Expression of intracellular iron transport protein transferrin receptor 1 was increased in the renal tubules of Aldo mice compared with control mice. Dietary iron restriction attenuated the development of hypertension and renal injury in aldosterone/salt-induced hypertensive mice.

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Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease

Abstract: Taken together, these data uncover a novel effect of iron restriction on renal damage and hypertension through the inhibition of renal mineralocorticoid receptor signaling.

Cited by 34 publications

References 25 publications

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Aortic Iron Overload With Oxidative Stress and Inflammation in Human and Murine Abdominal Aortic Aneurysm

Iron restriction inhibits renal injury in aldosterone/salt-induced hypertensive mice

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