Urotensin II (Gillichthys mirabilis)

Purpose of review: Urotensin II is a highly conserved undecapeptide which is well represented in the nervous system, heart and kidney. This review summarizes recent studies on cardiovascular and renal pathophysiology of urotensin II and clinical studies exploring the role of this peptide in cardiovascular and renal diseases. Recent findings: Urotensin II was initially seen as a vasoconstrictor/cardiodepressant compound and implicated in myocardial and renal dysfunction. Emerging evidence in experimental models and in humans indicates that urotensin II may play a cardioprotective role in coronary heart disease and in chronic renal failure. Summary: Administration of urotensin II produces a cardiodepressant effect in normal rats but exerts beneficial renal hemodynamic effects and preserves myocardial contractility in rats with chronic volume overload. Both urotensin II and urotensin-related peptide exhibit a myocardial protective property in an ischemia-reperfusion injury model in the isolated perfused rat heart. In patients with acute cardiac ischemia, circulating urotensin II is lower than normal and low plasma urotensin II signals a higher risk of adverse clinical events following myocardial infarction. Similarly, low urotensin II appears linked to death, cardiomyopathy and cardiovascular complications in patients with advanced renal insufficiency.

Intervertebral disc degeneration (IDD) results from the dysfunction of nucleus pulposus (NP) cells and the exhaustion of NP progenitors (ProNPs). The cellular applications of NP cells during IDD are currently limited due to the lack of in vivo studies showing whether NP cells are heterogeneous and contain ProNPs throughout postnatal stages. In this study, single-cell RNA sequencing of purified NP cells is used to map four molecularly defined populations and urotensin II receptor (UTS2R)-expressing postnatal ProNPs is identified, which are markedly exhausted during IDD, in mouse and human specimens. The lineage tracing shows that UTS2R+ ProNPs preferentially resides in the NP periphery with its niche factor tenascin-C and give rise to functional NP cells. It is also demonstrated that transplanting UTS2R+ ProNPs with tenascin-C into injured intervertebral discs attenuate the progression of IDD. The study provides a novel NP cell atlas, identified resident ProNPs with regenerative potential, and revealed promising diagnostic and therapeutic targets for IDD.

Accumulating evidence indicate that the neuropeptide urotensin II and urotensin II receptors are expressed in subsets of mammal spinal motoneurons. In fact, a role for the peptide in the regulation of motoneuron function at neuromuscular junction has been suggested, while roles for urotensin II at central synapses in spinal cord have never been addressed. We found that urotensin II receptors were closely associated with cholinergic terminals apposed to a subset of motoneuron and non-motoneuron cell bodies in the ventral horn of the adult mouse cervical spinal cord; urotensin II receptor was also expressed on non-cholinergic nerve terminals. In particular, urotensin II receptor appeared associated with both large cholinergic C-boutons and standard cholinergic terminals contacting some motoneuron perikarya. Cholinergic nerve terminals from mouse cervical spinal cord were equipped with functional presynaptic urotensin II receptors linked to excitation of acetylcholine release. In fact, functional experiments conducted on cervical spinal synaptosomes demonstrated a urotensin II evoked calcium-dependent increase in [(3)H]acetylcholine release pharmacologically verified as consistent with activation of urotensin II receptors. In spinal cord these actions would facilitate cholinergic transmission. These data indicate that, in addition to its role at the neuromuscular junction, urotensin II may control motor function through the modulation of motoneuron activity within the spinal cord.