Biology subjects

Hill, R. Z.

Publications and source records attributed to Hill, R. Z..

4 recordsLinked to original sources

bioRxiv2023

Renal mechanotransduction is an essential regulator of renin

The kidneys tightly control the composition of our internal environment to maintain homeostasis in the face of external variability. The regulation of blood volume begins in the kidneys and is essential for vertebrate life in terrestrial environments where salt and water availability are unpredictable1,2. Renin synthesis and release by juxtaglomerular granular cells of the kidney is the rate-limiting step in a hormonal cascade that modulates blood volume, filtration, and salt balance2. Renin is stimulated during hypovolemia and salt deprivation in response to chemical cues released from sympathetic efferent neurons and the macula densa onto the juxtaglomerular granular cells. Renin levels are also proposed to be modulated by mechanical forces elicited by changes in blood volume and/or pressure exerted upon juxtaglomerular cells2-4. However, the identity and significance of the juxtaglomerular mechanotransducer(s) was unknown. We found that the force-gated ion channel PIEZO2 is expressed in juxtaglomerular granular cells and in neighboring mesangial cells. Selective genetic ablation of PIEZO2 dysregulated the renin-angiotensin-aldosterone system by elevating renin, raising systemic blood pressure, inducing glomerular hyperfiltration, and exaggerating the hormonal response to volume depletion. These findings demonstrate that PIEZO2 contributes to renal blood volume sensing and kidney function in vivo.

physiology↗

bioRxiv2019

Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch.

immunology↗

bioRxiv2017

The signaling lipid sphingosine 1-phosphate regulates mechanical pain

Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds.

neuroscience↗

bioRxiv2017

S1PR3 mediates inflammatory pain and itch via distinct TRP channel-dependent pathways

Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid associated with a variety of chronic pain and itch disorders. S1P signaling has been linked to cutaneous pain, but its role in itch has not yet been studied. Here we find that S1P triggers itch and pain in mice in a concentration-dependent manner, with low levels triggering acute itch alone, and high levels triggering both pain and itch. Calcium imaging and electrophysiological experiments revealed that S1P signals via S1PR3 and TRPA1 in a subset of pruriceptors, and via S1PR3 and TRPV1 in a subset of heat nociceptors. And in behavioral assays, S1P-evoked itch was selectively lost in mice lacking TRPA1, whereas S1P-evoked acute pain and heat hypersensitivity were selectively lost in mice lacking TRPV1. We conclude that S1P acts via different cellular and molecular mechanisms to trigger itch and pain. Our discovery elucidates the diverse roles that S1P signaling plays in somatosensation and provides insight into how itch and pain are discriminated in the periphery.\n\nSignificance StatementItch and pain are major health problems with few effective treatments. Here, we show that the pro-inflammatory lipid S1P and its receptor S1PR3 trigger itch and pain behaviors via distinct molecular and cellular mechanisms. Our results provide a detailed understanding of the roles that S1P and S1PR3 play in somatosensation, highlighting their potential as targets for analgesics and antipruritics, and provide new insight into the mechanistic underpinnings of itch versus pain discrimination in the periphery.

neuroscience↗