Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy

Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear....

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Published in:Journal of the American Society of Nephrology 2015-10, Vol.26 (10), p.2434-2446
Main Authors: Yang, Ke, Wang, Cheng, Nie, Ling, Zhao, Xiaohui, Gu, Jun, Guan, Xu, Wang, Song, Xiao, Tangli, Xu, Xinli, He, Ting, Xia, Xuefeng, Wang, Junping, Zhao, Jinghong
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Animals
Basic Research
Female
Glucuronidase - blood
Glucuronidase - physiology
Glucuronidase - therapeutic use
Humans
Hypertrophy, Left Ventricular - blood
Hypertrophy, Left Ventricular - chemically induced
Hypertrophy, Left Ventricular - etiology
Hypertrophy, Left Ventricular - prevention & control
Indican - administration & dosage
Indican - blood
Indican - physiology
Male
Mice
Mice, Inbred C57BL
Middle Aged
Renal Insufficiency, Chronic - blood
Renal Insufficiency, Chronic - complications
Young Adult
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creator Yang, Ke
Wang, Cheng
Nie, Ling
Zhao, Xiaohui
Gu, Jun
Guan, Xu
Wang, Song
Xiao, Tangli
Xu, Xinli
He, Ting
Xia, Xuefeng
Wang, Junping
Zhao, Jinghong
description Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=-0.59, P
doi_str_mv 10.1681/ASN.2014060543
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Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=-0.59, P&lt;0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P&lt;0.001; for Klotho: r=-0.49, P&lt;0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal-regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD.</description><identifier>ISSN: 1046-6673</identifier><identifier>EISSN: 1533-3450</identifier><identifier>DOI: 10.1681/ASN.2014060543</identifier><identifier>PMID: 25804281</identifier><language>eng</language><publisher>United States: American Society of Nephrology</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Basic Research ; Female ; Glucuronidase - blood ; Glucuronidase - physiology ; Glucuronidase - therapeutic use ; Humans ; Hypertrophy, Left Ventricular - blood ; Hypertrophy, Left Ventricular - chemically induced ; Hypertrophy, Left Ventricular - etiology ; Hypertrophy, Left Ventricular - prevention &amp; control ; Indican - administration &amp; dosage ; Indican - blood ; Indican - physiology ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Renal Insufficiency, Chronic - blood ; Renal Insufficiency, Chronic - complications ; Young Adult</subject><ispartof>Journal of the American Society of Nephrology, 2015-10, Vol.26 (10), p.2434-2446</ispartof><rights>Copyright © 2015 by the American Society of Nephrology.</rights><rights>Copyright © 2015 by the American Society of Nephrology 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-47c7f0563d2809a5fce9f4f399417a222bd854c783e40202b8440d833894a83e3</citedby><cites>FETCH-LOGICAL-c435t-47c7f0563d2809a5fce9f4f399417a222bd854c783e40202b8440d833894a83e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587686/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587686/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25804281$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Ke</creatorcontrib><creatorcontrib>Wang, Cheng</creatorcontrib><creatorcontrib>Nie, Ling</creatorcontrib><creatorcontrib>Zhao, Xiaohui</creatorcontrib><creatorcontrib>Gu, Jun</creatorcontrib><creatorcontrib>Guan, Xu</creatorcontrib><creatorcontrib>Wang, Song</creatorcontrib><creatorcontrib>Xiao, Tangli</creatorcontrib><creatorcontrib>Xu, Xinli</creatorcontrib><creatorcontrib>He, Ting</creatorcontrib><creatorcontrib>Xia, Xuefeng</creatorcontrib><creatorcontrib>Wang, Junping</creatorcontrib><creatorcontrib>Zhao, Jinghong</creatorcontrib><title>Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy</title><title>Journal of the American Society of Nephrology</title><addtitle>J Am Soc Nephrol</addtitle><description>Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. 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In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal-regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. 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Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=-0.59, P&lt;0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P&lt;0.001; for Klotho: r=-0.49, P&lt;0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal-regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD.</abstract><cop>United States</cop><pub>American Society of Nephrology</pub><pmid>25804281</pmid><doi>10.1681/ASN.2014060543</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record>
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subjects Adolescent
Adult
Aged
Aged, 80 and over
Animals
Basic Research
Female
Glucuronidase - blood
Glucuronidase - physiology
Glucuronidase - therapeutic use
Humans
Hypertrophy, Left Ventricular - blood
Hypertrophy, Left Ventricular - chemically induced
Hypertrophy, Left Ventricular - etiology
Hypertrophy, Left Ventricular - prevention & control
Indican - administration & dosage
Indican - blood
Indican - physiology
Male
Mice
Mice, Inbred C57BL
Middle Aged
Renal Insufficiency, Chronic - blood
Renal Insufficiency, Chronic - complications
Young Adult
title Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy
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