Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex

Ihara, Jittoku; Huang, Yibin; Takami, Yoichi; Nozato, Yoichi; Takahashi, Toshimasa; Kakino, Akemi; Wang, Cheng; Wang, Ziwei; Guo, Yu; Liu, Weidong; Yin, Nanxiang; Ohara, Ryoichi; Fujimoto, Taku; Yoshida, Shino; Hongyo, Kazuhiro; Koriyama, Hiroshi; Akasaka, Hiroshi; Takeshita, Hikari; Sakai, Shinsuke; Inoue, Kazunori; Isaka, Yoshitaka; Rakugi, Hiromi; Sawamura, Tatsuya; Yamamoto, Koichi

doi:https://doi.org/10.7554/eLife.98766

Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex

Ihara, Jittoku; Huang, Yibin; Takami, Yoichi et al.

eLife, 2025, 13, R377

Number of Access:2,900（2025-08-16 00:38 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100742

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Title	Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex
Creator	CreatorName Ihara, Jittoku
	CreatorName Huang, Yibin
	NRID 1000090621756 1000090621756 ORCID 0000-0001-9018-6707 0000-0001-9018-6707 researchmap permalink YT-1973 YT-1973 Scopus Author ID 8635744100 8635744100 CreatorName Takami, Yoichi
	NRID 1000050880390 1000050880390 researchmap permalink ynozato87 ynozato87 Scopus Author ID 57199545575 57199545575 CreatorName Nozato, Yoichi
	NRID 1000060807270 1000060807270 researchmap permalink ToshimasaTakahashi ToshimasaTakahashi CreatorName Takahashi, Toshimasa
	NRID 1000000534637 1000000534637 CreatorName Kakino, Akemi
	CreatorName Wang, Cheng
	CreatorName Wang, Ziwei
	CreatorName Guo, Yu
	CreatorName Liu, Weidong
	CreatorName Yin, Nanxiang
	CreatorName Ohara, Ryoichi
	NRID 1000010854284 1000010854284 researchmap permalink tfujimoto0319 tfujimoto0319 CreatorName Fujimoto, Taku
	NRID 1000080962612 1000080962612 researchmap permalink Shino_Yoshida Shino_Yoshida CreatorName Yoshida, Shino
	NRID 1000070817155 1000070817155 researchmap permalink khongyo1860 khongyo1860 Scopus Author ID 55175070700 55175070700 CreatorName Hongyo, Kazuhiro
	NRID 1000060710093 1000060710093 researchmap permalink Hiroshi-Koriyama Hiroshi-Koriyama CreatorName Koriyama, Hiroshi
	NRID 1000070468081 1000070468081 researchmap permalink hiroshi-akasaka hiroshi-akasaka Scopus Author ID 35445539600 35445539600 CreatorName Akasaka, Hiroshi
	NRID 1000010791577 1000010791577 researchmap permalink HikariT HikariT CreatorName Takeshita, Hikari
	NRID 1000060817360 1000060817360 CreatorName Sakai, Shinsuke
	NRID 1000010631301 1000010631301 researchmap permalink kznri kznri Scopus Author ID 55124465800 55124465800 CreatorName Inoue, Kazunori
	NRID 1000000379166 1000000379166 researchmap permalink isaka-handai3857 isaka-handai3857 Scopus Author ID 16207611100 16207611100 ORCID 0000-0002-0820-7167 0000-0002-0820-7167 CreatorName Isaka, Yoshitaka
	NRID 1000020252679 1000020252679 ORCID 0000-0001-6508-4338 0000-0001-6508-4338 researchmap permalink read0042763 read0042763 Scopus Author ID 57202699453 57202699453 CreatorName Rakugi, Hiromi
	NRID 1000030243033 1000030243033 CreatorName Sawamura, Tatsuya
	NRID 1000000528424 1000000528424 ORCID 0000-0003-0107-9315 0000-0003-0107-9315 researchmap permalink kymt0410 kymt0410 Scopus Author ID 55624482466 55624482466 CreatorName Yamamoto, Koichi
Description	Ihara Jittoku, Huang Yibin, Takami Yoichi, et al. Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex. eLife 13, R377 (2025); https://doi.org/10.7554/eLife.98766.
Abstract	Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.
Publisher	eLife Sciences Publications, Ltd
Source Title	eLife
Volume (Issue)	13
Page	R377
Date of Issued	2025-03-25
Handle URL	https://hdl.handle.net/11094/100742
eISSN	2050084X
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.7554/eLife.98766
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	eLife. 2025, 13, p. R377
DC.title	Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex
DC.creator	Ihara, Jittoku
	Huang, Yibin
	Takami, Yoichi
	Nozato, Yoichi
	Takahashi, Toshimasa
	Kakino, Akemi
	Wang, Cheng
	Wang, Ziwei
	Guo, Yu
	Liu, Weidong
	Yin, Nanxiang
	Ohara, Ryoichi
	Fujimoto, Taku
	Yoshida, Shino
	Hongyo, Kazuhiro
	Koriyama, Hiroshi
	Akasaka, Hiroshi
	Takeshita, Hikari
	Sakai, Shinsuke
	Inoue, Kazunori
	Isaka, Yoshitaka
	Rakugi, Hiromi
	Sawamura, Tatsuya
	Yamamoto, Koichi
DC.publisher	eLife Sciences Publications, Ltd
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-03-25
DC.identifier	https://doi.org/10.7554/eLife.98766
DC.description	Ihara Jittoku, Huang Yibin, Takami Yoichi, et al. Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex. eLife 13, R377 (2025); https://doi.org/10.7554/eLife.98766.
DCTERMS.abstract	Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	100742
citation_title	Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex
citation_author	Ihara, Jittoku
	Huang, Yibin
	Takami, Yoichi
	Nozato, Yoichi
	Takahashi, Toshimasa
	Kakino, Akemi
	Wang, Cheng
	Wang, Ziwei
	Guo, Yu
	Liu, Weidong
	Yin, Nanxiang
	Ohara, Ryoichi
	Fujimoto, Taku
	Yoshida, Shino
	Hongyo, Kazuhiro
	Koriyama, Hiroshi
	Akasaka, Hiroshi
	Takeshita, Hikari
	Sakai, Shinsuke
	Inoue, Kazunori
	Isaka, Yoshitaka
	Rakugi, Hiromi
	Sawamura, Tatsuya
	Yamamoto, Koichi
citation_publisher	eLife Sciences Publications, Ltd
citation_date	2025-03-25
citation_journal_title	eLife
citation_volume	13
citation_firstpage	R377
citation_doi	https://doi.org/10.7554/eLife.98766
citation_public_url	https://hdl.handle.net/11094/100742

Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex

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