L ow protein diets reverse the urea concentration gradient in the renal inner medulla. To investigate the mechanism(s) for this change, we studied urea transport and cell ultrastructure in initial and terminal inner medullary collecting ducts (IMCD) from rats fed 18% protein or an isocaloric, 8% protein diet for 4 wk. Serum urea, aldosterone, and albumin were significantly lower in rats fed 8% protein, but total protein and potassium were unchanged. Vasopressin stimulated passive urea permeability (Purea) threefold (P < 0.05) in initial IMCDs from rats fed 8% protein, but not from rats fed 18% protein. Luminal phloretin reversibly inhibited vasopressin-stimulated Purea. However, in terminal IMCDs from rats fed either diet, vasopressin stimulated Purea. Net transepithelial urea flux (measured with identical perfusate and bath solutions) was found only in initial IMCDs from rats fed 8% protein. Reducing the temperature reversibly inhibited it, but phloretin did not. Electron microscopy of initial IMCD principal cells from rats fed 8% protein showed expanded Golgi bodies and prominent autophagic vacuoles, and morphometric analysis demonstrated a marked increase in the surface density and boundary length of the basolateral plasma membrane. These ultrastructural changes were not observed in the terminal IMCD. Thus, 8% dietary protein causes two new urea transport processes to appear in initial but not terminal IMCDs. This is the first demonstration that "active" urea transport can be induced in a mammalian collecting duct segment.