The angiotensin II (Ang II)–endothelin-1 (ET-1) axis is a key driver of hypertension (HTN), vascular dysfunction, and renal injury. Ang II stimulates ET-1 synthesis, while ET-1 amplifies Ang II signaling, creating a pathological loop that promotes vasoconstriction, oxidative stress, endothelial dysfunction, and fibrosis. The contribution of gut microbial metabolites to this pathway remains poorly understood. We hypothesized that indole-3-acetic acid (IAA), a tryptophan-derived microbial metabolite previously shown by our laboratory to inhibit endothelin-converting enzyme-1 (ECE-1) and antagonize ETAR/ETBR signaling, would attenuate Ang II–induced hypertension and minimize vascular and renal injury. To test this, mice aortic endothelial cells were chronically stimulated with 100 nanomolar (nM) Ang II and treated with graded concentrations of IAA (0.01–100 nM). ET-1 production, ECE-1 expression, ROS generation, NADPH oxidases, and inflammatory cytokines were analyzed using ELISA, Western blot, and fluorescence assays. In vivo, male Sprague Dawley rats were infused with Ang II (700 nanogram (ng)/kilogram (kg)/minute (min) for 14 days) and treated orally with IAA (5, 10, or 20 milligram (mg)/kg/day). Blood pressure was assessed by tail-cuff and validated by telemetry. Plasma ET-1 levels were quantified using ELISA, and vascular ET-1 expression was evaluated in isolated arteries. Endothelial function and vascular structure were assessed via pressure myography, while renal injury and fibrosis were evaluated histologically. IAA significantly inhibited Ang II–stimulated ECE-1, ET-1, ROS, NADPH oxidases, and cytokine production in vitro, demonstrating suppression of endothelial activation. In vivo, IAA at 10 and 20 mg/kg markedly attenuated Ang II–induced hypertension and preserved acetylcholine-mediated vasodilation. Smooth muscle responsiveness to nitric oxide remained intact, indicating protection of sGC signaling. IAA also prevented resistance artery remodeling by reducing media thickness and wall-to-lumen ratio. Importantly, IAA significantly lowered ET-1 concentrations in plasma and reduced vascular ET-1 expression, confirming systemic and tissue-level inhibition of the ET-1 pathway. In the kidney, IAA decreased interstitial fibrosis. These findings demonstrate that IAA disrupts the Ang II–ET-1 pathological axis, reduces hypertension, and protects against vascular and renal injury. By targeting ET-1 biosynthesis and signaling, this gut microbial metabolite offers a promising strategy for mitigating Ang II–driven cardiovascular and renal pathology. American Heart Association This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Ezewudo et al. (Fri,) studied this question.