P170 OXIDIZED LOW-DENSITY LIPOPROTEIN POTENTIATES ANGIOTENSIN II-INDUCED GQ ACTIVATION THROUGH THE AT1 - LOX1 RECEPTOR COMPLEX

Background and Objective: Chronic kidney disease (CKD) and atherosclerotic heart disease, often associated with dyslipidemia and hypertension, represent significant health concerns. This study investigates 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. The hypothesis is that oxLDL enhances Ang II-induced Gq signaling via the AT1-LOX1 receptor complex. Methods Experiments were conducted using CHO cells and renal cell models. The effects of oxLDL and Ang II on Gq-mediated inositol phosphate 1 production and calcium influx were examined in cells expressing both lectin-like oxLDL receptor (LOX-1) and Ang II receptor type 1 (AT1), and in cells expressing only AT1. Additionally, conformational studies using AT1 biosensors were performed. In vivo studies involved wild-type mice and LOX-1 knockout mice fed a high-fat diet with Ang II infusion. Results: 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. AT1 biosensors 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 showed exacerbated renal injury, whereas LOX-1 knockout mice did not. Conclusions: The findings suggest a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 receptor complex, driving renal injury in CKD. This study highlights a novel mechanism of renal injury in CKD driven by dyslipidemia and hypertension and suggests the therapeutic potential of targeting the AT1-LOX1 receptor complex in patients with these comorbidities.