Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Science Translational Medicine Année : 2022

Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice

Alicja Czopek
Peter Gallacher
Dan Pugh
  • Fonction : Auteur
Jessica Ivy
Emily Godden
Robert Hunter
James Dear
Matthew Bailey
Neeraj Dhaun

Résumé

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 threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated 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 Ly6C high 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 proinflammatory Ly6C high monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6C low 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 sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.

Dates et versions

Identifiants

Citer

Alicja Czopek, Rebecca Moorhouse, Peter Gallacher, Dan Pugh, Jessica Ivy, et al.. Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice. Science Translational Medicine, 2022, 14 (675), ⟨10.1126/scitranslmed.abf5074⟩. ⟨hal-03918227⟩

Collections

UP-SANTE
20 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More