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Acute kidney injury

New antagonist prevents I/R injury

Nature Reviews Nephrology volume 11, page 631 (2015)Cite this article

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Pharmacologic antagonism of the mineralocorticoid receptor is effective in preventing acute kidney injury (AKI) after ischaemia/reperfusion (I/R), but the underlying mechanisms and the renal cell types targeted by mineralocorticoid receptor antagonists (MRAs) were previously unknown. Now, research by Frédéric Jaisser and colleagues shows that BR-4628 (a novel non-steroidal MRA) protects against oxidant damage induced by renal I/R, and that its beneficial effects can be blocked by a selective endothelin B receptor (ETB) antagonist.

The researchers administered BR-4628 to a rat model of transient bilateral renal I/R and examined the effects on renal injury and the endothelin pathway, as pre-pro-endothelin-1 is upregulated following I/R-induced AKI. Firstly, the researchers found that administration of BR-4628 before or 3 h after I/R was efficient in preventing renal injury and in improving renal function, as verified by histologic assessment and molecular analysis of markers of apoptosis, inflammation, and tubular injury. Secondly, the researchers noted that I/R induced inactivation of ETB in their model by sulfenic acid modification, which consequently decreased eNOS activity and nitric oxide production. Consequently, rats co-administered BR-4628 and an ETB antagonist maintained elevated creatinine levels and exhibited histologic indicators of renal injury, thus supporting a direct action of BR-4628 on ETB activation.

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References

  1. Barrera-Chimal, J. et al. Sulfenic acid moficiation of endothelin B receptor is responsible for the benefit of a nonsteroidal mineralocorticoid receptor antagonist in renal ischemia. J. Am. Soc. Nephrol. 10.1681/ASN.2014121216

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  1. Jessica K. Edwards
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Edwards, J. New antagonist prevents I/R injury. Nat Rev Nephrol 11, 631 (2015). https://doi.org/10.1038/nrneph.2015.161

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