Inhibition of Renin Release, a Crucial Event in Homeostasis, is Mediated by Coordinated Calcium Oscillations within Juxtaglomerular Cell Clusters.

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 Ca, preventing excessive circulating renin and hypertension. However, within their native structural organization, the intricacies of intracellular Ca signaling dynamics and their sources remain uncharacterized.

METHODS

We generated mice expressing the JG cell-specific genetically encoded Ca indicator (GCaMP6f) to investigate Ca dynamics within JG cell clusters and . For Ca imaging, acutely prepared kidney slices were perfused continuously with a buffer containing variable Ca and AngII concentrations ± Ca channel inhibitors. For Ca image capture, native mouse kidneys were imaged using multi-photon microscopy with and without AngII administration. ELISA measurements of renin concentrations determined acute renin secretion and , respectively.

RESULTS

Ca 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 spikes, which inversely correlated with renin secretion. Pharmacological channel inhibition identified key sources of these oscillations: endoplasmic reticulum Ca storage and release, extracellular Ca uptake via ORAI channels, and intercellular communication through gap junctions. Blocking ORAI channels and gap junctions reduced AngII inhibitory effect on renin secretion. Ca imaging demonstrated robust intracellular and intercellular Ca oscillations within JG cell clusters under physiological conditions, exhibiting spike patterns consistent with those measured in preparations. Administration of AngII enhanced the Ca oscillatory signals and suppressed acute renin secretion .

CONCLUSION

AngII elicits coordinated intracellular and intercellular Ca oscillations within JG cell clusters, and . The effect is driven by endoplasmic reticulum-derived Ca release, ORAI channels, and gap junctions, leading to suppressed renin secretion.