Renin Cell Baroreceptor, a Nuclear Mechanotransducer Central for Homeostasis.
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ABSTRACT:
SUBMITTER: Watanabe H
PROVIDER: S-EPMC8273135 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Publications
Renin Cell Baroreceptor, a Nuclear Mechanotransducer Central for Homeostasis.
Watanabe Hirofumi H Belyea Brian C BC Paxton Robert L RL Li Minghong M Dzamba Bette J BJ DeSimone Douglas W DW Gomez R Ariel RA Sequeira-Lopez Maria Luisa S MLS
Circulation research 20210517 2
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Project description:BackgroundThe blood pressure (BP) regulatory impact of the arterial baroreflex has been well established in health and disease. Under normotensive conditions, we have previously demonstrated functional differences in the central processing of the left versus right aortic baroreceptor afferent input. However, it is unknown if lateralization in aortic baroreflex function remains evident during hypertension.MethodWe therefore, investigated the effects of laterality on the expression of baroreflex-driven cardiovascular reflexes in a genetic model of essential hypertension, the spontaneously hypertensive rat (SHR). Anesthetized male SHRs (total n = 9) were instrumented for left, right, and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, and 0.4 mA for 20 s) and measurement of mean arterial pressure (MAP), heart rate (HR), mesenteric vascular resistance (MVR), and femoral vascular resistance (FVR).ResultsLeft right, and bilateral ADN stimulation evoked frequency-dependent decreases in MAP, HR, MVR, and FVR. Left and bilateral ADN stimulation evoked greater reflex reductions in MAP, HR, MVR, and FVR compared with right-sided stimulation. Reflex bradycardia to bilateral stimulation was larger relative to both left-sided and right-sided stimulation. Reflex depressor and vascular resistance responses to bilateral stimulation mimicked those of the left-sided stimulation. These data indicate a left-side dominance in the central integration of aortic baroreceptor afferent input. Furthermore, reflex summation due to bilateral stimulation is only evident on the reflex bradycardic response, and does not drive further reductions in BP, suggesting that reflex depressor responses in the SHRs are primarily driven by changes in vascular resistance.ConclusionTogether, these results indicate that lateralization in aortic baroreflex function is not only evident under normotensive conditions but also extends to hypertensive conditions.
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Project description:Aminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET) channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media. Two-photon imaging of Texas Red conjugated gentamicin (GTTR) uptake into live hair cells was rapid and selective. Hypocalcemia, which increases the open probability of MET channels, increased AG entry into hair cells. Three blockers of MET channels (curare, quinine, and amiloride) significantly reduced GTTR uptake, whereas the endocytosis inhibitor concanavalin A did not. Dynosore quenched the fluorescence of GTTR and could not be tested. Pharmacologic blockade of MET channels with curare or quinine, but not concanavalin A or dynosore, prevented hair cell loss when challenged with gentamicin for up to 96 hours. Taken together, data indicate that the patency of MET channels mediated AG entry into hair cells and its toxicity. Results suggest that limiting permeation of AGs through MET channel or preventing their entry into endolymph are potential therapeutic targets for preventing hair cell death and hearing loss.
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Project description:Renin cells are crucial for survival - they control fluid-electrolyte and blood pressure homeostasis, vascular development, regeneration, and oxygen delivery to tissues. During embryonic development, renin cells are progenitors for multiple cell types that retain the memory of the renin phenotype. When there is a threat to survival, those descendants are transformed and reenact the renin phenotype to restore homeostasis. We tested the hypothesis that the molecular memory of the renin phenotype resides in unique regions and states of these cells' chromatin. Using renin cells at various stages of stimulation, we identified regions in the genome where the chromatin is open for transcription, mapped histone modifications characteristic of active enhancers such as H3K27ac, and tracked deposition of transcriptional activators such as Med1, whose deletion results in ablation of renin expression and low blood pressure. Using the rank ordering of super-enhancers, epigenetic rewriting, and enhancer deletion analysis, we found that renin cells harbor a unique set of super-enhancers that determine their identity. The most prominent renin super-enhancer may act as a chromatin sensor of signals that convey the physiologic status of the organism, and is responsible for the transformation of renin cell descendants to the renin phenotype, a fundamental process to ensure homeostasis.
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Project description:We explored the effects of baroreceptor afferents laterality and sexual dimorphism on the expression of cardiovascular reflex responses to baroreflex activation in Sprague Dawley (SD) rats. Under urethane anesthesia, rats of either sex (total n = 18) were instrumented for left, right and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, 0.4 mA for 20 s) and measurement of mean arterial pressure (MAP), heart rate (HR) and mesenteric (MVR) and femoral (FVR) vascular resistance. Female rats were matched for the diestrus phase of the estrus cycle. Left, right and bilateral ADN stimulation evoked frequency-dependent drops in MAP, HR, and MVR, and increases in FVR. Irrespective of sex, left and bilateral ADN stimulation as compared to right-sided stimulation mediated greater reflex reductions in MAP, HR, and MVR but not in FVR. In males, reflex bradycardic responses were greater in response to bilateral stimulation relative to both left- and right-sided stimulation. In females, left ADN stimulation evoked the largest increase in FVR. Left and bilateral ADN stimulations evoked greater reductions in MAP and MVR while left-sided stimulation produced larger increases in FVR in females compared with males. All other reflex responses to ADN stimulation were relatively comparable between males and females. These results show a differential baroreflex processing of afferent neurotransmission promoted by left versus right baroreceptor afferent inputs and sexual dimorphism in the expression of baroreflex responses in rats of either sex. Collectively, these data add to our understanding of physiological mechanisms pertaining to baroreflex control in both males and females.
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Project description:Kidney function and blood pressure homeostasis are regulated by purinergic signaling mechanisms. These autocrine/paracrine signaling pathways are initiated by the release of cellular ATP, which influences kidney hemodynamics and steady-state renin secretion from juxtaglomerular cells. However, the mechanism responsible for ATP release that supports tonic inputs to juxtaglomerular cells and regulates renin secretion remains unclear. Pannexin 1 (Panx1) channels localize to both afferent arterioles and juxtaglomerular cells and provide a transmembrane conduit for ATP release and ion permeability in the kidney and the vasculature. We hypothesized that Panx1 channels in renin-expressing cells regulate renin secretion in vivo. Using a renin cell-specific Panx1 knockout model, we found that male Panx1 deficient mice exhibiting a heightened activation of the renin-angiotensin-aldosterone system have markedly increased plasma renin and aldosterone concentrations, and elevated mean arterial pressure with altered peripheral hemodynamics. Following ovariectomy, female mice mirrored the male phenotype. Furthermore, constitutive Panx1 channel activity was observed in As4.1 renin-secreting cells, whereby Panx1 knockdown reduced extracellular ATP accumulation, lowered basal intracellular calcium concentrations and recapitulated a hyper-secretory renin phenotype. Moreover, in response to stress stimuli that lower blood pressure, Panx1-deficient mice exhibited aberrant "renin recruitment" as evidenced by reactivation of renin expression in pre-glomerular arteriolar smooth muscle cells. Thus, renin-cell Panx1 channels suppress renin secretion and influence adaptive renin responses when blood pressure homeostasis is threatened.
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Project description:Hair cells detect vibrations of their stereociliary bundle by activation of mechanically sensitive transducer channels. Although evidence suggests the transducer channels are near the stereociliary tops and are opened by force imparted by tip links connecting contiguous stereocilia, the exact channel site remains controversial. We used fast confocal imaging of fluorescence changes reflecting calcium entry during bundle stimulation to localize the channels. Calcium signals were visible in single stereocilia of rat cochlear inner hair cells and were up to tenfold larger and faster in the second and third stereociliary rows than in the tallest first row. The number of functional stereocilia was proportional to transducer current amplitude, indicating that there were about two channels per stereocilium. Comparable results were obtained in outer hair cells. The observations, supported by theoretical simulations, suggest there are no functional mechanically sensitive transducer channels in first row stereocilia and imply the channels are present only at the bottom of the tip links.
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