Schematic 1

In the diseased kidney tubules, increased Cx43 hemichannel activity is linked to an increase in priming and activation of the NRLP3 inflammasome via NFκB and ATP mediated P2 × 7R activity respectively. This chain of events culminates in caspase 1 mediated cleavage of IL1β, IL18 and activation of downstream inflammatory mediators. In the face of persistent NLRP3 activation, Cx43 hemichannels remain open, perpetuating a viscous cycle of events in which NFκB mediated NLRP3 priming, increases Cx43 expression, with P2X7R mediated NLRP3 activation increasing [Ca²⁺]_i and downstream inflammation. Peptide5 successfully blocks these ATP-driven events, decreasing NLRP3 priming and activation. These observations are paralleled by a reduction in tubule inflammation and paracrine mediated signaling, as evidenced by a reduction in the secretion of soluble signaling mediators, decreased fibroblast activation and reduced macrophage number