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

• Published in: Science translational medicine 2022-12, Vol.14 (675), p.eabf5074-eabf5074
• Main Authors: Czopek, Alicja, Moorhouse, Rebecca, Gallacher, Peter J, Pugh, Dan, Ivy, Jessica R, Farrah, Tariq E, Godden, Emily, Hunter, Robert W, Webb, David J, Tharaux, Pierre-Louis, Kluth, David C, Dear, James W, Bailey, Matthew A, Dhaun, Neeraj
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - complications; Animals; Blood pressure; Cardiovascular diseases; Chronic illnesses; Complications; Disease Progression; Endothelin 1; Endothelin ETB receptors; Endothelin-1 - metabolism; Endothelin-1 - pharmacology; Endothelin-1 - therapeutic use; Endothelins - metabolism; Endothelins - pharmacology; Endothelins - therapeutic use; Endothelium; Fibrosis; Human health and pathology; Inflammation; Ischemia; Ischemia - complications; Kidney - metabolism; Kidney diseases; Life Sciences; Lymphocytes B; Mice; Microvasculature; Monocytes; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - drug therapy
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abf5074

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 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 monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6C 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.