Novel Proinflammatory Function of Renal Intercalated Cells

Abstract

Background: Serious and often fatal acute kidney injury (AKI) is frequently seen after major surgery, local and remote organ damage, and sepsis. It is associated with uncontrolled inflammation, and is usually diagnosed only after the kidneys have gone through significant and often irreversible damage. Summary: During our work involving another type of kidney disease that leads to acid-base disorders of the blood, we unexpectedly found high levels of a protein called the P2Y₁₄ “purinergic” receptor, in specialized kidney epithelial cells called intercalated cells (ICs). These cells are responsible for maintaining whole body acid-base balance by regulating the secretion of excess protons into the urine, which normalizes blood pH. However, it turns out that the P2Y₁₄ receptor in these cells responds to a molecule called uridine diphosphate (UDP)-glucose, which is a danger signal released by damaged cells anywhere in the body. When UDP-glucose reaches the kidney, it stimulates ICs to produce chemoattractant cytokines; this results in renal inflammation and contributes to the onset of AKI. Key Message: Thus, our work now points to ICs as key mediators of renal inflammation and AKI, following surgery and/or damage to remote organs, sepsis, and also local insults to the kidney itself. The link between the proton secreting ICs of the kidney and AKI is an example of how a fundamental research project with a defined aim, in this case understanding acid-base homeostasis, can lead to a novel observation that has unexpected but major implications in another area of human health.

Proinflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice

“…Similarly, injection of UDP-Glc into the mouse uterus induced a 5-fold increase in the number of neutrophils present in the endometrium (41). Furthermore, we previously showed that collecting duct intercalated cells (ICs) are sensors of UDP-Glc and mediate the recruitment of neutrophils into the kidney via activation of the P2Y14 receptor located on their apical membrane (42,47).…”

Mannan-binding lectin serine protease-2 (MASP-2) in human kidney and its relevance for proteolytic activation of the epithelial sodium channel

“…Thus, a direct intracellular interaction between ENaC and MASP2 is not likely under physiological conditions. Previous studies have suggested that the intercalated cells play a role in the innate immune system 41 ; however, the role of MASP-2 in intercalated cells is unknown. The mechanism for selective accumulation of zymogen MASP-2 in intercalated cells is not clear.…”

Control of Directed Cell Migration after Tubular Cell Injury by Nucleotide Signaling

“…The ligand-gated ionotropic cation channel P2X4 and P2X7 appear to exacerbate ischemic AKI by triggering pro-inflammatory cytokine production and NLRP3 inflammasome activation [ 37 , 38 ]. Similarly, G protein-coupled metabotropic P2Y14, expressed in intercalated cells of the nephron, generate chemoattractant cytokines in response to uridine glucose, resulting in renal inflammation [ 39 ]. In contrast, P2RY2 receptor ameliorates renal fibrosis after subtotal nephrectomy [ 40 ], alleviates cerebral ischemia–reperfusion injury [ 24 ], and confers the beneficial effects of uridine-5′-triphosphate after myocardial infarction [ 41 ].…”