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Targeting inflammation in AKI by P2Y14 receptor inhibition in mice

Acute kidney injury (AKI) is common among hospitalized patients and is frequently associated with immune cell infiltration into the kidney. Now, Sylvie Breton and colleagues show that inhibition of the P2Y14 receptor reduces inflammation and attenuates AKI following ischaemia–reperfusion injury (IRI). They also report a correlation between urinary levels of the P2Y14 receptor ligand, uridine diphosphate-glucose (UDP-Glc) and the development of AKI among patients in the intensive care unit (ICU).

The mechanism by which trauma to a distant organ or the kidney itself can lead to AKI is a topic of much debate. In previous work, Breton and colleagues implicated UDP-Glc as a damage-signalling molecule involved in this process. “When released from damaged or stressed tissues, UDP-Glc activates P2Y14 within the kidney, triggering an inflammatory cascade,” says Breton. “The cascade then creates a self-reinforcing cycle that causes further kidney inflammation, ultimately leading to AKI.” The researchers now show that the pro-inflammatory response of intercalated cells to IRI and subsequent recruitment of macrophages and monocytes is attenuated by pharmacological or genetic inhibition of P2Y14 in mice. Moreover, inhibition of P2Y14 reduced the extent of proximal tubule damage and indices of kidney dysfunction.

To assess the relevance of this pathway, the researchers investigated urinary UDP-Glc levels and outcomes of patients admitted to the ICU. “Our longitudinal pilot study showed a striking correlation between urinary levels of UDP-Glc and a subsequent AKI diagnosis in ICU patients, particularly among patients undergoing cardiac surgery,” explains Breton. “Not only do our findings suggest that urinary UDP-Glc may serve as a biomarker of AKI, they also provide mechanistic insights into the inflammatory storm that can lead to AKI”.


Original article

  1. Battistone, M. A. et al. Pro-inflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice. J. Clin. Invest. (2020)

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Correspondence to Susan J. Allison.

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Allison, S.J. Targeting inflammation in AKI by P2Y14 receptor inhibition in mice. Nat Rev Nephrol 16, 372 (2020).

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