The Role of the Endothelin System in the Progression of Acute Kidney Injury to Chronic Kidney Disease

Abstract

IntroductionAcute kidney injury (AKI) is the most common cause of organ dysfunction in critically ill patients, increasing the risk of developing chronic kidney disease (CKD) by 30%. Endothelin‐1 (ET‐1) is the most potent endogenous vasoconstrictor mediating its effects through two receptors – the endothelin‐A receptor (ETA) and endothelin‐B receptor (ETB). The ET system is upregulated in AKI and CKD. We investigated the role of the ET system in the progression of AKI to CKD using the renal ischemia‐reperfusion injury (IRI) model.MethodsStudy 150 min of unilateral IRI was induced by occlusion of the left renal pedicle in male FVB mice. Starting 24h after injury, mice received either 4 weeks of sitaxentan (a selective ETA receptor antagonist; n=12) or vehicle (n=12) in drinking water. Blood pressure (BP) was recorded continuously over the 4‐week period via radiotelemetry and kidney fibrosis assessed at the end.Study 2Using a similar protocol, mice received either sitaxentan (n=8) or vehicle (n=8) for 5 days after which animals were anesthetized and BP measured using a carotid artery cannula, and renal cortical and medullary blood flows measured in the IRI kidney by laser Doppler flowmetry. We assessed systemic and renal hemodynamic responses to brief intravenous infusion of angiotensin II (ANG II).ResultsStudy 1Unilateral renal IRI led to a sustained increase in BP of ~8 mmHg and significant fibrosis within the IRI kidney. Sitaxentan completely prevented this BP rise and the development of fibrosis.Study 2In healthy mice, brief ANG II infusion increased systemic BP and reduced renal cortical and medullary blood flow. Unilateral renal IRI enhanced the BP rise seen with ANG II infusion and significantly attenuated the falls in renal cortical and medullary blood flow in the IRI kidney. 5 days of sitaxentan treatment improved the renal hemodynamic response to ANG II.ConclusionsWe have demonstrated that administration of a selective ETA receptor antagonist improves the perturbations in systemic and renal hemodynamic seen in a model of AKI transitioning to CKD. These may be of important therapeutic benefit and should be pursued in a clinical trial in relevant patient groups.Support or Funding InformationThis work was funded by the British Heart Foundation and the Medical Research Council.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.