Urotensin-II
Also known as: U-II, Urotensin II, UII, urotensin-2, hU-II, human urotensin II
Cyclic neuropeptide; vasoactive peptide hormone; endogenous GPCR ligand
What it is
Urotensin-II is a small cyclic peptide studied by researchers interested in cardiovascular disease, heart failure, kidney disease, and metabolic syndrome. It acts on receptors throughout the heart, blood vessels, and kidneys, and is being investigated as a potential drug target rather than a therapeutic agent itself.
The scientific side
Urotensin-II (U-II) is an 11-amino-acid cyclic neuropeptide that exerts its effects by binding to UT, a Gq-coupled G protein-coupled receptor formerly designated GPR14. UT is widely expressed in the cardiovascular system, kidneys, central nervous system, adrenal gland, pancreas, and other tissues. Upon binding UT, U-II activates Gq-mediated signaling that releases intracellular calcium from the endoplasmic reticulum, activating downstream pathways including MAPK cascades (JNK, ERK), RhoA/GEF-H1/myosin light chain phosphorylation, and nuclear factor-kB. These intracellular signals produce vasoconstriction of vascular smooth muscle, cardiomyocyte hypertrophy, and proliferation of vascular smooth muscle cells and fibroblasts. In blood vessels, U-II action is bidirectional: it causes potent endothelium-independent vasoconstriction but can also elicit endothelium-dependent vasodilation, and the net effect depends on species, vascular bed, vessel caliber, and endothelial integrity. In diabetic or endothelium-denuded vessels, the vasoconstrictive response is markedly amplified. U-II promotes acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) activity, foam cell formation, and inflammatory cell chemotaxis, implicating it in atherosclerosis. In the kidney, U-II-UT signaling on podocytes stimulates TRPC6 channel-mediated ER calcium release, induces ER stress, disrupts the actin cytoskeleton, and drives lipid dysregulation, albuminuria, glomerular and tubular fibrosis, and podocyte foot process effacement. U-II and its closely related endogenous ligand urotensin II-related peptide (URP) are generated from inactive precursors by plasma kallikrein and other serine proteases including factor XIa, plasmin, and thrombin. Elevated plasma and tissue levels of U-II and upregulated UT expression have been documented across hypertension, heart failure, atherosclerosis, pulmonary hypertension, diabetes, chronic kidney disease, and metabolic syndrome, making the UT receptor an actively studied drug target.
Class: Cyclic neuropeptide; vasoactive peptide hormone; endogenous GPCR ligand
Administration & storage
- Administration
- Intravenous (IV) — used in acute hemodynamic and pharmacological studiesIntraperitoneal (IP) — used in rodent model studiesTopical iontophoresis — used in human skin microvessel tone studies (NCT00654966)
- Storage
- Research-grade synthetic U-II peptides are typically stored lyophilized at -20°C, protected from light and moisture. Reconstituted solutions should be aliquoted and stored at -80°C; repeated freeze-thaw cycles reduce peptide integrity. Stability data for human use formulations are not available in the reviewed literature.
Legal & regulatory status
Not approved for any therapeutic indication. Used as a pharmacological research tool in investigational studies only.
Not listed on the current WADA Prohibited List. No evidence of use in sport performance contexts identified in the literature reviewed.
No approved indication. Research use only.
What it's studied for
- Cardiovascular disease and hypertension (biomarker and therapeutic target research) Preclinical / Observational clinical
- Heart failure (disease pathophysiology and UT antagonist drug development) Preclinical / Early clinical
- Chronic kidney disease and diabetic nephropathy (UT antagonism as reno-protective strategy) Preclinical / Early clinical
- Metabolic syndrome and obesity (UII system dysregulation) Preclinical / Observational clinical
- Steatohepatitis and hepatic fibrosis (UTR antagonism) Preclinical
- Endotoxic shock and inflammatory injury (UT receptor blockade) Preclinical
- Diabetic vascular dysfunction (UT antagonism in endothelial dysfunction) Preclinical
- Pulmonary hypertension (elevated U-II expression) Observational clinical
Safety signals
- Potent vasoconstrictive response — risk of severe hemodynamic compromise at high doses
- Cardiomyocyte hypertrophy and myocardial remodeling
- Renal glomerular injury — podocyte ER stress and foot process effacement
- Pro-inflammatory and pro-fibrotic tissue remodeling
- Enhanced vasoconstriction in endothelial dysfunction and diabetes
- Promotion of atherosclerotic foam cell formation and smooth muscle cell proliferation
- Inhibition of insulin secretion and metabolic dysregulation
- Mortality increase in endotoxic shock models at certain UT signaling conditions
No peer-reviewed studies indexed for this peptide yet.
Frequently asked
Is Urotensin-II available as a peptide I can purchase and self-administer?
Urotensin-II is a research-grade peptide used exclusively in laboratory and investigational settings. It is not approved for human therapeutic use by any regulatory authority, and there are no established human dosing or self-administration protocols. Its extreme potency as a vasoconstrictor makes unsupervised use potentially dangerous. We cannot provide guidance on sourcing or self-administering this peptide.
How does Urotensin-II differ from endothelin-1 as a vasoconstrictor?
Based on the reviewed research, Urotensin-II is generally considered even more potent than endothelin-1 in certain vascular beds, though unlike endothelin-1, its vasoconstrictive effects are highly species- and vascular-bed-dependent. In rat aorta, the effect is strongest proximal to the aortic arch and diminishes toward peripheral arteries. Both peptides activate Ca2+-dependent smooth muscle contraction, but U-II acts specifically through the UT (GPR14) receptor, whereas endothelin-1 acts via ET-A and ET-B receptors.
What diseases are associated with elevated Urotensin-II levels?
According to published research, elevated circulating Urotensin-II has been documented in patients with hypertension, atherosclerosis, congestive heart failure, pulmonary hypertension, chronic kidney disease, diabetic nephropathy, type 2 diabetes, metabolic syndrome, and liver cirrhosis with portal hypertension. In most of these conditions, U-II overactivity is thought to contribute to disease progression rather than being merely a biomarker, but the causal relationships are still being investigated.
Are there any UT receptor antagonist drugs in clinical development?
Several UT receptor antagonists have reached preclinical and early clinical stages. Palosuran and SB-611812 have been studied preclinically and in early human trials. SAR101099 (Sanofi) reached Phase I clinical studies with a reported good safety and tolerability profile and showed reno- and cardioprotective effects in preclinical models. However, as of the research reviewed here, no UT antagonist has received regulatory approval for any indication.
Does Urotensin-II have any role in kidney protection?
The reviewed evidence actually points in the opposite direction: Urotensin-II signaling through the UT receptor appears to promote kidney injury rather than protection. UT deletion in mice attenuated high-fat-diet-induced albuminuria, glomerular fibrosis, and podocyte damage. Pharmacological blockade of UT with agents like SAR101099 reduced proteinuria and improved survival in preclinical chronic kidney disease models. Blocking U-II signaling — not adding it — is the strategy being explored for kidney protection.
What is the relationship between Urotensin-II and the UT receptor's signaling pathways?
Based on the reviewed abstracts, U-II binds the Gq-coupled UT receptor (GPR14), which triggers intracellular Ca2+ release from the endoplasmic reticulum via inositol trisphosphate. This activates downstream signaling through JNK, ERK, and p38 MAPK cascades, RhoA/GEF-H1/myosin light chain phosphorylation (producing smooth muscle contraction), NF-kB (driving inflammation), and TRPC6 channels in podocytes. The receptor can also stabilize distinct conformations when bound by U-II versus the related peptide URP, leading to differential (biased) signaling through Gq versus G12 pathways.