Iron chelation and a free radical scavenger suppress angiotensin II‐induced downregulation of <i>klotho</i>, an anti‐aging gene, in rat

Saito, Kan; Ishizaka, Nobukazu; Mitani, Hiroki; Ohno, Minoru; Nagai, Ryozo

doi:10.1016/s0014-5793(03)00894-9

Cited by 79 publications

(78 citation statements)

References 16 publications

(20 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…10 We found that Ang II-induced aberrant iron homeostasis may have modulatory effects on the extent of urinary protein excretion 10 and on the expression of genes that have relation to anti-aging 14 and fibrogenesis. 11 However, notably, in situ hybridization showed that the localization of upregulation of TGF-␤1 mRNA and deposition of iron were found to occur in different renal tubular cells.…”

Section: Discussionmentioning

confidence: 90%

Lipid Accumulation and Transforming Growth Factor-β Upregulation in the Kidneys of Rats Administered Angiotensin II

et al. 2005

Self Cite

View full text Add to dashboard Cite

Abstract-Abnormal lipid metabolism may play a role in progressive renal failure. We studied whether lipid accumulation occurs and whether lipid deposits are colocalized with transforming growth factor-␤1 (TGF-␤1) in the kidney of angiotensin II-infused animals. Oil red O staining showed marked lipid deposition in the tubular epithelial and vascular wall cells of angiotensin II-treated but not in norepinephrine-treated rats. Histological analyses showed that increased amounts of superoxide and intense TGF-␤1 mRNA expression were present in lipid-positive tubular epithelial cells in angiotensin II-infused animals. Protein expression of sterol regulatory element-binding protein 1 (SREBP-1) and mRNA expression of fatty acid synthase in the kidney were Ϸ3 times and 1.5 times, respectively, higher in angiotensin II-treated rats than in controls. Treatment of angiotensin II-infused animals with an iron chelator, deferoxamine, attenuated the angiotensin II-induced increases in renal expression of SREBP-1 and fatty acid synthase and normalized the lipid content in the renal cortical tissues. Abnormal lipid metabolism may be associated with upregulation of TGF-␤1 expression and aberrant iron homeostasis in the kidneys of angiotensin II-infused animals. Key Words: angiotensin II Ⅲ transforming growth factors Ⅲ lipids P revious studies showed that accumulation of lipids in nonadipose tissues occurs in certain diseased conditions, and that it plays a crucial role in the pathogenesis of tissue damage, 1 a phenomenon referred to as lipotoxicity. 2 For example, lipid deposition in the arterial wall 3,4 is postulated to represent an early event in the development of atherosclerosis. 5 The accumulation of triglycerides (TGs) in cardiomyocytes 6,7 may be associated with contractile dysfunction, and excess TGs in the liver may promote hepatic fibrosis. 8 Lipid accumulation in the kidney may represent features of glomerular and tubulointerstitial damage. 9 We found that long-term administration of angiotensin II (Ang II) to rats caused marked deposition of iron 10 and upregulation of the expression of transforming growth factor-␤1 (TGF-␤1) in renal tubular epithelial cells. 11 We also found that iron chelation attenuated the Ang II-induced upregulation of TGF-␤1 in the kidney, suggesting a possible link between aberrant iron homeostasis and TGF-␤1 upregulation. However, unexpectedly, histological analysis showed that upregulation of TGF-␤1 mRNA and deposition of iron occurred in different tubular cells in most cases. The aims of the present study were to investigate whether accumulation of lipids occurs in the kidney of Ang II-infused animals and to investigate the relationship between lipid accumulation and TGF-␤1 in terms of localization. We also investigated whether Ang II infusion alter the expression of genes that have relation to the lipid metabolism, such as ATP-binding cassette transporter subfamily A-1 (ABCA1), scavenger receptor class B type 1 (SR-B1), sterol regulatory elementbinding protein 1 (SREBP-1), SREBP-2, 3-hydrox...

show abstract

Section: Discussionmentioning

confidence: 90%

Lipid Accumulation and Transforming Growth Factor-β Upregulation in the Kidneys of Rats Administered Angiotensin II

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…The rat TGF-␤1 cDNA probe was a kind gift from Dr. Shiow-Shih Tang (Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts) and Dr. John S. D. Chan (Centre Hospitalier de l'Université de Montréal-Hôtel-Dieu, Mon-treal, Quebec, Canada). Rat collagen type I cDNA was obtained by subcloning the RT-PCR product using rat kidney mRNA and validated by DNA sequencing using the dideoxyribonucleotide sequencing method, as described previously (27). These cDNA probes were labeled with [␣-32 P]dCTP (Amersham Life Sciences, Piscataway, NJ) using commercial kits (Nippon Gene, Toyama, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…We previously showed that plasma levels of 8-epi-prostaglandin F 2␣ (8-epi-PGF 2␣ ), a reliable marker of in vivo oxidative stress, are increased in response to ANG II infusion (2); furthermore, this ANG II-induced increase in plasma 8-epi-PGF 2␣ is inhibited by the treatment with deferoxamine (27), which suggests that iron metabolism is involved in the enhancement of ANG II-induced oxidative stress. In these experiments, however, hydralazine, which did not completely suppress the ANG II-induced upregulation of hepatic TGF-␤1 mRNA upregulation in the current study, also suppressed the ANG II-induced increase in plasma 8-epi-PGF 2␣ levels (2).…”

Section: E Fmentioning

confidence: 99%

Administration of ANG II induces iron deposition and upregulation of TGF-β1 mRNA in the rat liver

Ishizaka¹,

Saito²,

Noiri³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

show abstract

“…Direct effect(s) of RAS components on 1␣-hydroxylase or VDR have not been found; however, ANG II reduces renal KLOTHO expression (286,348,443,453), which interferes with FGF23 signaling and results in elevated FGF23 levels (reviewed in Ref. 97).…”

Section: The Klotho-vitamin D-ras Connectionmentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

show abstract

Iron chelation and a free radical scavenger suppress angiotensin II‐induced downregulation of klotho, an anti‐aging gene, in rat

Cited by 79 publications

References 16 publications

Lipid Accumulation and Transforming Growth Factor-β Upregulation in the Kidneys of Rats Administered Angiotensin II

Lipid Accumulation and Transforming Growth Factor-β Upregulation in the Kidneys of Rats Administered Angiotensin II

Administration of ANG II induces iron deposition and upregulation of TGF-β1 mRNA in the rat liver

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Contact Info

Product

Resources

About