To further delineate the mechanisms involved in the renal compensatory response to renal mass ablation, we evaluated the interactions of protein intake and uninephrectomy on total, active, and passive fluid absorption (Jv) in the in vitro perfused superficial proximal straight tubule (SFPST) isolated from sham-operated or uninephrectomized rabbits pair fed 7, 14, or 45% protein diets. In all protein groups, we observed significant increases in Jv and in cell height from SFPST segments obtained from remnant renal tissue harvested 3 wk post-uninephrectomy when compared with sham-operated controls. Uninephrectomy also led to compensatory hypertrophy of whole-kidney mass and to elevations in inulin clearances. Increased protein intake consistently enhanced these renal and SFPST structural and functional changes, whereas protein restriction limited compensatory responses. The changes in Jv following uninephrectomy were attributable to increases in the active, but not the passive, component of Jv in all protein groups. Moreover, the active component of Jv could be modified by altering dietary protein intake. Single kidney inulin clearances were correlated with the changes in total Jv with ultrafiltrate perfusate (r = 0.88; P less than 0.025), with artificial perfusate (r = 0.95; P less than 0.01), the active component of Jv (r = 0.96; P less than 0.005), SFPST cell height (r = 0.94; P less than 0.01), and whole-kidney weight (r = 0.99; P less than 0.005). These results indicate that hypertrophy of renal structure and augmentation of function following uninephrectomy and increased dietary protein are also observed in single rabbit SFPST segments perfused in vitro; that the hypertrophic responses following uninephrectomy can be enhanced or reduced by increases or decreases in protein intake, respectively; and that these changes are paralleled by changes in glomerular filtration rate.