Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex
Jittoku Ihara,
Yibin Huang,
Yoichi Takami,
Yoichi Nozato,
Toshimasa Takahashi,
Akemi Kakino,
Cheng Wang,
Ziwei Wang,
Yu Guo,
Weidong Liu,
Nanxiang Yin,
Ryoichi Ohara,
Taku Fujimoto,
Shino Yoshida,
Kazuhiro Hongyo,
Hiroshi Koriyama,
Hiroshi Akasaka,
Hikari Takeshita,
Shinsuke Sakai,
Kazunori Inoue,
Yoshitaka Isaka,
Hiromi Rakugi,
Tatsuya Sawamura,
Koichi Yamamoto
Affiliations
Jittoku Ihara
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Yibin Huang
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Medicine, University of Toronto, Toronto, Canada
Akemi Kakino
Department of Molecular Pathophysiology, Shinshu University Graduate School of Medicine, Matsumoto, Japan
Cheng Wang
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Ziwei Wang
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Yu Guo
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Weidong Liu
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Nanxiang Yin
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Ryoichi Ohara
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Taku Fujimoto
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Shino Yoshida
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Kazuhiro Hongyo
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Hiroshi Koriyama
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Hiroshi Akasaka
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Hikari Takeshita
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Shinsuke Sakai
Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
Kazunori Inoue
Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
Yoshitaka Isaka
Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
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.