{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:18:35Z","timestamp":1785449915889,"version":"3.56.0"},"posted":{"date-parts":[[2024,12,23]]},"group-title":"Cell Biology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>\n                    Juxtaglomerular (JG) cells are sensors that control blood pressure (BP) and fluid-electrolyte homeostasis. They are arranged as clusters at the tip of each afferent arteriole. In response to a decrease in BP or extracellular fluid volume, JG cells secrete renin, initiating an enzymatic cascade that culminates in the production of angiotensin II (AngII), a potent vasoconstrictor that restores BP and fluid-electrolyte homeostasis. In turn, AngII exerts negative feedback on renin release concomitantly with increased intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , preventing excessive circulating renin and hypertension. However, within their native structural organization, the intricacies of intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling dynamics and their sources remain uncharacterized.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    We generated mice expressing the JG cell-specific genetically encoded Ca\n                    <jats:sup>2+<\/jats:sup>\n                    indicator (GCaMP6f) to investigate Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dynamics within JG cell clusters\n                    <jats:italic>ex vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . For\n                    <jats:italic>ex vivo<\/jats:italic>\n                    Ca\n                    <jats:sup>2+<\/jats:sup>\n                    imaging, acutely prepared kidney slices were perfused continuously with a buffer containing variable Ca\n                    <jats:sup>2+<\/jats:sup>\n                    and AngII concentrations \u00b1 Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel inhibitors. For\n                    <jats:italic>in vivo<\/jats:italic>\n                    Ca\n                    <jats:sup>2+<\/jats:sup>\n                    image capture, native mouse kidneys were imaged\n                    <jats:italic>in situ<\/jats:italic>\n                    using multi-photon microscopy with and without AngII administration. ELISA measurements of renin concentrations determined acute renin secretion\n                    <jats:italic>ex vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , respectively.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Ex vivo<\/jats:italic>\n                    Ca\n                    <jats:sup>2+<\/jats:sup>\n                    imaging revealed that JG cells exhibit robust and coordinated intracellular oscillatory signals with cell-cell propagation following AngII stimulation. AngII dose-dependently induced stereotypical burst patterns characterized by consecutive Ca\n                    <jats:sup>2+<\/jats:sup>\n                    spikes, which inversely correlated with renin secretion. Pharmacological channel inhibition identified key sources of these oscillations: endoplasmic reticulum Ca\n                    <jats:sup>2+<\/jats:sup>\n                    storage and release, extracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake via ORAI channels, and intercellular communication through gap junctions. Blocking ORAI channels and gap junctions reduced AngII inhibitory effect on renin secretion.\n                    <jats:italic>In vivo<\/jats:italic>\n                    Ca\n                    <jats:sup>2+<\/jats:sup>\n                    imaging demonstrated robust intracellular and intercellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    oscillations within JG cell clusters under physiological conditions, exhibiting spike patterns consistent with those measured in\n                    <jats:italic>ex vivo<\/jats:italic>\n                    preparations. Administration of AngII enhanced the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    oscillatory signals and suppressed acute renin secretion\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSION<\/jats:title>\n                  <jats:p>\n                    AngII elicits coordinated intracellular and intercellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    oscillations within JG cell clusters,\n                    <jats:italic>ex vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . The effect is driven by endoplasmic reticulum-derived Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release, ORAI channels, and gap junctions, leading to suppressed renin secretion.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.12.23.629519","type":"posted-content","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T23:50:14Z","timestamp":1734997814000},"source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of Renin Release, a Crucial Event in Homeostasis, is Mediated by Coordinated Calcium Oscillations within Juxtaglomerular Cell Clusters"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2409-7401","authenticated-orcid":false,"given":"Hiroki","family":"Yamaguchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2539-1346","authenticated-orcid":false,"given":"Nick A.","family":"Guagliardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0659-5650","authenticated-orcid":false,"given":"Laura A.","family":"Bell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2880-9165","authenticated-orcid":false,"given":"Manako","family":"Yamaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2164-0555","authenticated-orcid":false,"given":"Daisuke","family":"Matsuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5330-7392","authenticated-orcid":false,"given":"Fang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2688-0988","authenticated-orcid":false,"given":"Jason P.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5801-9997","authenticated-orcid":false,"given":"Mohamed","family":"Diagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5731-1219","authenticated-orcid":false,"given":"Lucas F.","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8516-0788","authenticated-orcid":false,"given":"Silvia","family":"Medrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2052-3899","authenticated-orcid":false,"given":"Paula Q.","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2154-6224","authenticated-orcid":false,"given":"Edward H.","family":"Nieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5124-8255","authenticated-orcid":false,"given":"R. 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