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

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 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 proinflammatory 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 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. Description The endothelin system is up-regulated in AKI, and blocking its effects prevents the transition to chronic kidney and cardiovascular disease. Suppressing sequelae of acute kidney injury Suppressing sequelae of acute kidney injuryAcute kidney injury (AKI) can progress to chronic kidney disease (CKD), and there are no treatments that can reduce the risk of this progression. Here, Czopek and colleagues identified sustained upregulation of the endothelin system in patients suffering from AKI. In mouse models of ischemia-reperfusion injury, inhibition of the endothelin system through selective antagonism of the endothelin-A receptor early after injury and continuing for four weeks largely prevented the transition from AKI to CKD, resulting in reduced inflammation and oxidative stress, along with a protective immune response. These findings suggest that inhibition of the endothelin system early after AKI might be beneficial in preventing development of CKD in patients.--MN