Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis

Abstract

Kidney function and blood pressure homeostasis are regulated by purinergic signaling mechanisms. These autocrine/paracrine signaling pathways are initiated by the release of cellular ATP, which influences kidney hemodynamics and steady-state renin secretion from juxtaglomerular cells. However, the mechanism responsible for ATP release that supports tonic inputs to juxtaglomerular cells and regulates renin secretion remains unclear. Pannexin 1 (Panx1) channels localize to both afferent arterioles and juxtaglomerular cells and provide a transmembrane conduit for ATP release and ion permeability in the kidney and the vasculature. We hypothesized that Panx1 channels in renin-expressing cells regulate renin secretion in vivo. Using a renin cell-specific Panx1 knockout model, we found that male Panx1 deficient mice exhibiting a heightened activation of the reninangiotensin-aldosterone system have markedly increased plasma renin and aldosterone concentrations, and elevated mean arterial pressure with altered peripheral hemodynamics. Following ovariectomy, female mice mirrored the male phenotype. Furthermore, constitutive Panx1 channel activity was observed in As4.1 reninsecreting cells, whereby Panx1 knockdown reduced extracellular ATP accumulation, lowered basal intracellular calcium concentrations and recapitulated a hyper-secretory renin phenotype. Moreover, in response to stress stimuli that lower blood pressure, Panx1-deficient mice exhibited aberrant "renin recruitment" as evidenced by reactivation of renin expression in pre-glomerular arteriolar smooth muscle cells. Thus, renin-cell Panx1 channels suppress renin secretion and influence adaptive renin responses when blood pressure homeostasis is threatened.

Flexible and multifaceted: the plasticity of renin-expressing cells

“…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 ]. Another cell adhesion molecule essential for mediating cell–cell or cell–matrix interactions is β1-integrin, which is abundantly expressed in the kidneys including renin-lineage cells.…”

Amount of Pannexin 1 in smooth muscle cells regulates sympathetic nerve induced vasoconstriction

“…As a control to rule out ATP secretion by connexins, we found that the Cx43 peptide inhibitor Gap19 did not affect EFS-induced constriction (Figure 4D-F and Supplemental Figure 6). Genetic Panx1 deletion has been used to demonstrate an important role in blood pressure regulation by renin-secreting cells 18 (where genetic deletion causes hypertension) and by SMC 3 (where genetic deletion causes hypotension). Because iSMC Panx1 OE mice displayed increased EFS induced vasoconstriction we hypothesized these mice would have elevated blood pressure.…”

Pannexin 1 as a driver of inflammation and ischemia–reperfusion injury

“…The vast majority of work has focused on Panx1 as an ATP channel, with multiple stimuli inducing ATP secretion as a paracrine signaling pathway. However, physiologic roles for Panx1 are not limited to secretion, as more recent evidence has shown that Panx1 can also act as a plasma membrane calcium channel, increasing cytosolic calcium in response to stimuli, such as TNFα [ 29 , 30 ]. Several other solutes have been shown to be transmitted through Panx1 including fluorescent tracers, anandamide, lactate, glutamate, spermidine, and bacterial products, consistent with roles for Panx1 in multiple different signaling pathways [ 26 , 27 , 31 – 33 ].…”

“…This is in comparison to constitutive phosphorylation of Y198 on the intracellular loop of Panx1 which was found to be important for Panx1 channel opening. A mimetic peptide against this region (“PxIL2P”) was able to inhibit Panx1 current, ATP release, and alpha-adrenergic vasoconstriction; more general Panx1 inhibition was also noted in endothelium and renin-secreting cells [ 5 – 7 , 30 , 49 , 59 ]. Although the Y308 site has not been found to be as important in terms of plasma membrane localization or trafficking, it is similar to Y198, in that it was important for gating properties, including ATP release and current [ 10 , 60 ].…”

“…Panx1 is present throughout the kidney, especially in the vasculature, apical membranes of proximal tubules, collecting ducts, and thick descending limbs [ 100 ]. Regulation of ATP levels by Panx1 mediated release in the kidney is essential under physiological conditions, since it regulates renal hemodynamics and tubular transport in addition to pathological conditions [ 101 ]. Pharmacological and genetic screening methods of assessing the effects of Panx1 on renal IRI [ 14 ], a mouse model of AKI, revealed that global, endothelial, and epithelial tissue-specific deletion of Panx1 had a protective effect, as did pharmacological inhibition of Panx1 channels during AKI [ 14 , 102 ].…”