Pannexins in Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is highly prevalent among hospitalized patients and is associated with serious consequences with limited pharmacological treatment options. Pannexin 1 (Panx1) channel is a ubiquitously expressed nonselective membrane transport channel that efficiently effluxes ATP and plays a central role in the progression of inflammatory diseases. Animal models that target Panx1 through pharmacological inhibition or genetic deficiency have better outcomes in minimizing inflammation and associated pathology. Given the involvement of Panx1 at multiple steps of -inflammatory pathology, Panx1 could be a potential therapeutic target in the treatment of AKI. Further research is needed in elaborating the mechanisms and identifying Panx1-specific inhibitor molecules to better understand the role of Panx1 in AKI pathology arising due to diverse insults.

Keywords: ATP; Acute kidney injury; Adenosine; Mitochondria; Pannexins; Purinergic signaling.

Figure 1:. Panx1 and ATP contribute to inflammation:

Panx1 and ATP play central roles in the inflammatory pathway. During injury, activation of Panx1 channel causes efflux of extracellular ATP, which activates the purinergic P2X and P2Y signaling pathway and initiates inflammation. Extracellular ATP can also be cleaved by CD39 to from ADP, AMP, which is then converted into adenosine by CD73. Adenosine binds with to A2A adenosine receptors that leads to an anti-inflammatory effect. Cytoplasmic calcium influx due to purinergic signaling can alter mitochondrial function. Intracellular ATP is necessary for maintenance of mitochondrial function, autophagy and cell survival. Activation of Panx1 channel causes reduced intracellular ATP pool which negatively affects cell survival. Panx1 channel in endoplasmic reticulum acts as leaky calcium channel and aids in intracellular calcium influx.