Projects per year
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.
|Journal||Science Translational Medicine|
|Publication status||Published - 14 Dec 2022|
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Research Excellence Award Number 3
1/04/19 → 31/03/24
The burden of cardiovascular disease in patients with kidney disease: temporal trends and treatment gaps
1/02/21 → 31/01/23
21st century imaging for large vessel vasculitis
Dhaun, N. & Pugh, D.
UK central government bodies/local authorities, health and hospital authorities
1/08/19 → 31/12/21