Connexin Hemichannels Contribute to the Activation of cAMP Signaling Pathway and Renin Production

Abstract

Connexin hemichannels play an important role in the control of cellular signaling and behaviors. Given that lowering extracellular Ca2+, a condition that activates hemichannels, is a well-characterized stimulator of renin in juxtaglomerular cells, we, therefore, tested a potential implication of hemichannels in the regulation of renin in As4.1 renin-secreting cells. Lowering extracellular Ca2+ induced hemichannel opening, which was associated with cAMP signaling pathway activation and increased renin production. Blockade of hemichannels with inhibitors or downregulation of Cxs with siRNAs abrogated the activation of cAMP pathway and the elevation of renin. Further analysis revealed that cAMP pathway activation was blocked by adenylyl cyclase inhibitor SQ 22536, suggesting an implication of adenyl cyclase. Furthermore, the participation of hemichannels in the activation of the cAMP signaling pathway was also observed in a renal tubular epithelial cell line NRK. Collectively, our results characterized the hemichannel opening as a presently unrecognized molecular event involved in low Ca2+-elicited activation of cAMP pathway and renin production. Our findings thus provide novel mechanistic insights into the low Ca2+-initiated cell responses. Given the importance of cAMP signaling pathway in the control of multiple cellular functions, our findings also highlight the importance of Cx-forming channels in various pathophysiological situations.

Alteration of Cx37, Cx40, Cx43, Cx45, Panx1, and Renin Expression Patterns in Postnatal Kidneys of Dab1-/- (yotari) Mice

“…In our study, we found high Cx40 expression in the cortex of yotari mice in P4 and it was significantly higher in regard to wt, while consequently renin expression dramatically increased in the cortex of P14 yotari mice. This finding is in accordance with the previous report that disturbance of Cx40 intercellular signaling may lead to a disbalance of blood pressure control through renin secretion and hypertension onset [ 39 ]. Genetic loss-of-function defects of Cx40 in renal JG cells have been associated with renin-dependent hypertension [ 42 ].…”

“…This provides a broader network of activity and intercellular communication concerning Cx control of renin secretion. Recently, Hong and Yao proposed that using strategies such as specific siRNA or Cxs mimetic peptides might lead to the development of more effective approaches in the control of renin secretion in vivo [ 39 ]. In the last decade, the role of gap junctions in the control of renin has been extensively investigated and multiple lines of evidence have shown that Cx40 channels are required for regulatory mechanisms of renin secretion and associated with correct localization of cells that express renin [ 19 ].…”

“…Using the mouse renin-secreting cell line, Hong and Yao observed that activation of Cx hemichannels is an important step in low Ca 2+ induced activation of the cAMP pathway, and therefore induction of renin secretion. Additionally, blockade of Cx hemichannels or downregulation of Cxs in renin-secreting cells caused the termination of cAMP pathway activation [ 39 ]. In our study, we found high Cx40 expression in the cortex of yotari mice in P4 and it was significantly higher in regard to wt, while consequently renin expression dramatically increased in the cortex of P14 yotari mice.…”

Flexible and multifaceted: the plasticity of renin-expressing cells

“…A study, in which Cx40 was replaced by Cx45, however shows that not the expression of Cx40 itself is crucial for the regulation of renin release from juxtaglomerular cells but the gap junctional coupling with neighboring cells [ 98 ]. Moreover, not only cell–cell communication via gap junctions seems to be important for the regulation of renin secretion but also signaling via connexin hemichannels [ 36 ]. A recent study suggests that pannexin 1 could also be involved in the regulation of basal renin secretion through mediating intercellular communication [ 14 ].…”