Meprin A is a zinc-dependent metallo-endopeptidase that is present in the brush border membrane of renal proximal tubular epithelial cells. Although this enzyme has been detected in the kidney of mammalian species and its biochemical structure and action have been characterized, the role of this endopeptidase in normal renal physiology and in disease states is unknown. Therefore, we assessed the susceptibility of inbred strains of mice with normal and low meprin A activity to ischemic and nephrotoxic acute renal failure. We report that two normal meprin A strains of mice, C57BL/6 and DBA/2, developed more severe renal functional and structural injury following either bilateral renal artery clamping or the injection of hypertonic glycerol, compared to two low meprin A strains, C3H/He and CBA. These findings suggest that meprin A plays a role in the pathophysiology of acute renal failure following a variety of insults to the kidney. We propose that redistribution of this metalloendopeptidase to the basolateral membrane domain during acute renal failure results in degradation of the extracellular matrix and damage to adjacent peritubular structures.