An exaggerated inflammatory response is the hallmark of a plethora of disorders. ATP is a central signaling molecule that orchestrates the initiation and resolution of the inflammatory response by enhancing activation of the inflammasome, leukocyte recruitment and activation of T cells. ATP can be released from cells through pannexin (Panx) channels, a family of glycoproteins consisting of three members, Panx1, Panx2, and Panx3. Panx1 is ubiquitously expressed and forms heptameric channels in the plasma membrane mediating paracrine and autocrine signaling. Besides their involvement in the inflammatory response, Panx1 channels have been shown to contribute to different modes of cell death (i.e., pyroptosis, necrosis and apoptosis). Both genetic ablation and pharmacological inhibition of Panx1 channels decrease inflammation in vivo and contribute to a better outcome in several animal models of inflammatory disease involving various organs, including the brain, lung, kidney and heart. Up to date, several molecules have been identified to inhibit Panx1 channels, for instance probenecid (Pbn), mefloquine (Mfq), flufenamic acid (FFA), carbenoxolone (Cbx) or mimetic peptides like 10Panx1. Unfortunately, the vast majority of these compounds lack specificity and/or serum stability, which limits their application. The recent availability of detailed structural information on the Panx1 channel from cryo-electron microscopy studies may open up innovative approaches to acquire new classes of synthetic Panx1 channel blockers with high target specificity. Selective inhibition of Panx1 channels may not only limit acute inflammatory responses but may also prove useful in chronic inflammatory diseases, thereby improving human health. Here, we reviewed the current knowledge on the role of Panx1 in the initiation and resolution of the inflammatory response, we summarized the effects of Panx1 inhibition in inflammatory pathologies and recapitulate current Panx1 channel pharmacology with an outlook towards future approaches.

Dietary treatment is seminal for management of chronic kidney disease (CKD). The aim of our project was to assess the effects of potassium intake on the progression of CKD. We used 2 mouse CKD models to analyze the effects of potassium intake on CKD : the unilateral ureteral obstruction (UUO) and the POD-ATTAC models. POD-ATTAC mice display a podocyte-specific apoptosis after the administration of a chemical inducer. We also studied the effect of mineralocorticoid receptor (MR) using UUO in kidney tubule-specific MR knockout mice. In both UUO and POD-ATTAC mice, high potassium diet increased interstitial fibrosis. High potassium diet also increased the abundance of the extracellular matrix protein fibronectin and decreased the abundance of the epithelial marker Na+-K+ ATPase. Consistently, POD-ATTAC mice fed with high potassium diet displayed lower glomerular filtration rate. Spironolactone, a MR antagonist, decreased fibrosis induced by high potassium diet in POD-ATTAC mice. However, kidney tubule-specific MR knockout did not improve the fibrotic lesions induced by UUO under normal or high potassium diets. Macrophages from high potassium-fed POD-ATTAC mice displayed higher mRNA levels of the pro-inflammatory chemokine MCP1. This effect was decreased by spironolactone, suggesting a role of MR signaling in myeloid cells in the pro-fibrotic effect of potassium-rich diet. High potassium intake generates more fibrosis leading to decreased kidney function in experimental CKD. MR signaling plays a pivotal role in this potassium-induced fibrosis. The effect of reducing potassium intake on CKD progression should be assessed in future clinical trials.