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

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.

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.

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.

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.