Endothelin blockade prevents the long-term cardiovascular & renal sequelae of acute kidney injury

Alicja Czopek, Rebecca Moorhouse, Peter J Gallacher, Dan Pugh, Jess R Ivy, Tariq Farrah, Emily Godden, Robert W Hunter, David J Webb, Pierre Louis Tharaux, David C Kluth, James W Dear, Matthew A Bailey, Neeraj Dhaun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular/physiological pathways are poorly defined. There are no therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was 3-fold higher, urine endothelin-1 2-fold higher, and kidney preproendothelin-1, endothelin-A and endothelin-B receptor message upregulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6Chigh monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal pro-inflammatory Ly6Chigh monocytes and B-cells and promoted recruitment of anti-inflammatory Ly6Clow monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequalae of AKI in mice. Our study suggests that existing drugs, particularly those coupling vascular support and anti-inflammatory action, may improve outcomes in AKI. Our findings suggest upregulation of the endothelin system in patients with AKI. Preclinical studies support the use of drugs that block the endothelin system to improve outcomes in patients with AKI.
Original languageEnglish
JournalScience Translational Medicine
Publication statusPublished - 14 Dec 2022


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