bioRxiv : the preprint server for biology · 2025
Inhibition of Renin Release, a Crucial Event in Homeostasis, is Mediated by Coordinated Calcium Oscillations within Juxtaglomerular Cell Clusters.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Yamaguchi Hiroki, Guagliardo Nick A, Bell Laura A, Yamaguchi Manako, Matsuoka Daisuke, Xu Fang, Smith Jason P, Diagne Mohamed, Almeida Lucas F, Medrano Silvia, Barrett Paula Q, Nieh Edward H, Gomez R Ariel, Sequeira-Lopez Maria Luisa S
Аннотация
BACKGROUND: 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 Ca2+, preventing excessive circulating renin and hypertension. However, within their native structural organization, the intricacies of intracellular Ca2+ signaling dynamics and their sources remain uncharacterized.
METHODS: We generated mice expressing the JG cell-specific genetically encoded Ca2+ indicator (GCaMP6f) to investigate Ca2+ dynamics within JG cell clusters ex vivo and in vivo. For ex vivo Ca2+ imaging, acutely prepared kidney slices were perfused continuously with a buffer containing variable Ca2+ and AngII concentrations ± Ca2+ channel inhibitors. For in vivo Ca2+ image capture, native mouse kidneys were imaged in situ using multi-photon microscopy with and without AngII administration. ELISA measurements of renin concentrations determined acute renin secretion ex vivo and in vivo, respectively.
RESULTS: Ex vivo Ca2+ 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 Ca2+ spikes, which inversely correlated with renin secretion. Pharmacological channel inhibition identified key sources of these oscillations: endoplasmic reticulum Ca2+ storage and release, extracellular Ca2+ uptake via ORAI channels, and intercellular communication through gap junctions. Blocking ORAI channels and gap junctions reduced AngII inhibitory effect on renin secretion. In vivo Ca2+ imaging demonstrated robust intracellular and intercellular Ca2+ oscillations within JG cell clusters under physiological conditions, exhibiting spike patterns consistent with those measured in ex vivo preparations. Administration of AngII enhanced the Ca2+ oscillatory signals and suppressed acute renin secretion in vivo.
CONCLUSION: AngII elicits coordinated intracellular and intercellular Ca2+ oscillations within JG cell clusters, ex vivo and in vivo. The effect is driven by endoplasmic reticulum-derived Ca2+ release, ORAI channels, and gap junctions, leading to suppressed renin secretion.
METHODS: We generated mice expressing the JG cell-specific genetically encoded Ca2+ indicator (GCaMP6f) to investigate Ca2+ dynamics within JG cell clusters ex vivo and in vivo. For ex vivo Ca2+ imaging, acutely prepared kidney slices were perfused continuously with a buffer containing variable Ca2+ and AngII concentrations ± Ca2+ channel inhibitors. For in vivo Ca2+ image capture, native mouse kidneys were imaged in situ using multi-photon microscopy with and without AngII administration. ELISA measurements of renin concentrations determined acute renin secretion ex vivo and in vivo, respectively.
RESULTS: Ex vivo Ca2+ 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 Ca2+ spikes, which inversely correlated with renin secretion. Pharmacological channel inhibition identified key sources of these oscillations: endoplasmic reticulum Ca2+ storage and release, extracellular Ca2+ uptake via ORAI channels, and intercellular communication through gap junctions. Blocking ORAI channels and gap junctions reduced AngII inhibitory effect on renin secretion. In vivo Ca2+ imaging demonstrated robust intracellular and intercellular Ca2+ oscillations within JG cell clusters under physiological conditions, exhibiting spike patterns consistent with those measured in ex vivo preparations. Administration of AngII enhanced the Ca2+ oscillatory signals and suppressed acute renin secretion in vivo.
CONCLUSION: AngII elicits coordinated intracellular and intercellular Ca2+ oscillations within JG cell clusters, ex vivo and in vivo. The effect is driven by endoplasmic reticulum-derived Ca2+ release, ORAI channels, and gap junctions, leading to suppressed renin secretion.