These studies examined the effects of the volume expansion and the enhanced activity of the renin-angiotensin system during pregnancy on the severity of glycerol-induced myoglobinuric acute renal failure (ARF) in the rat. Renal cortical renin content (RCRC) and plasma renin concentration (PRC) were measured during the first, second, and third weeks of pregnancy. There were no significant changes in RCRC during pregnancy, but PRC was significantly elevated by the third week (22 ± 2 vs. 12 ± 2 ng angiotensin I/ml/h, p < 0.001), despite plasma volume expansion as assessed by changes in the hematocrit (37.7 ± 0.5 vs. 46.4 ± 0.6%, p < 0.001). Despite the elevated PRC, a significant reduction in the severity of ARF was seen during the third week of pregnancy, as assessed by both blood urea nitrogen and inulin clearance measurements. When a sustained natriuresis was superimposed earlier in pregnancy by saline drinking, significantly more protection against ARF was seen, but with less plasma volume expansion. These results suggest that the mechanism by which saline drinking confers protection may be independent of the degree of volume expansion but may be dependent upon the associated sustained natriuresis.