Background and Purpose: Endothelin-1 (ET1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in patients with chronic kidney disease (CKD), but their utility has been limited because of associated fluid retention and increased heart failure risk in patients with left ventricular dysfunction. Understanding mechanisms of fluid retention could result in solutions that preserve their renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging. Approach: We utilized a previously developed mathematical model of ET-1 kinetics, ETA antagonism, kidney function, and sodium and water homeostasis to evaluate mechanistic hypotheses of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD, and evaluated the model’s ability to predict observed decreases in hematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP) and estimated glomerular filtration rate (eGFR). Key Results: An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and hematocrit observed in RADAR. Conclusions and impact: These findings indicate that fluid retention with ETA antagonism may not be caused by a direct anti-diuresis effect within the kidney, but may instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.