Abstract
Epithelial cells constitute the 1st line of defense against pathogens, and their participation in innate immunity is rapidly emerging. In this mini-review, we discuss the noncanonical role of renal intercalated cells (ICs) in pathogen defense and in the initiation of sterile inflammation. This last function has strong implications in the onset of acute kidney injury (AKI), a potentially fatal medical complication that is seen in hospitalized patients. AKI is associated with inflammation, and it is often diagnosed only after the kidneys have suffered significant and often irreversible damage. While examining the regulation of proton secretion by type A ICs (A-ICs), we unexpectedly found high expression of the pro-inflammatory purinergic receptor P2Y14 in these cells. This receptor is located on the apical surface of A-ICs and binds UDP-glucose (UDP-Glc), a danger-associated molecular pattern molecule released from injured cells that is filtered by the glomeruli and is concentrated in the collecting duct lumen. UDP-Glc activates P2Y14 in A-ICs and triggers the production of chemokines that attract pro-inflammatory immune cells into the kidney stroma and aggravate ischemia-induced proximal tubule injury. Inhibition of P2Y14 or deletion of its gene specifically in ICs in a murine model of ischemia-reperfusion injury attenuated these effects. Thus, together with their previously recognized role in pathogen defense, A-ICs are now recognized as sensors and mediators of renal sterile inflammation that participate in the onset of AKI. Blocking the UDP-Glc/P2Y14 pathway in A-ICs provides new insights into the development of novel AKI therapeutics.