High protein diet is known to increase glomerular filtration rate (GFR) and induce kidney hypertrophy. The mechanisms underlying these changes are not understood. Since the mammalian kidney comprises different nephron segments located in well-delineated zones, it is conceivable that the hypertrophy does not affect all kidney zones and all nephron segments uniformly. The present experiments were designed to study the chronic effects of high or low isocaloric protein diets (HP = 32% or LP = 10% casein, respectively) on kidney function and morphology in Sprague-Dawley rats. HP diet induced significant increases in kidney mass, GFR, free water clearance, and maximum urine concentrating ability. Kidney hypertrophy was characterized by: 1. a preferential increase in thickness of the inner stripe of the outer medulla (IS) (+54%, P less than 0.001, while total kidney height, from cortex to papillary tip, increased only by 18%); 2. a marked hypertrophy of the thick ascending limbs (TAL) in the inner stripe (+40% epithelium volume/unit tubular length, P less than 0.05) but not in the outer stripe nor in the cortex; 3. an increase in heterogeneity of glomeruli between superficial (S) and deep (D) nephrons (D/S = 1.47 in HP vs. 1.17 in LP, P less than 0.05). In contrast, normal kidney growth with age and kidney hypertrophy induced by uninephrectomy were not accompanied by preferential enlargement of IS structures. The morphologic changes induced by high protein intake parallel those we previously reported in rats fed a normal diet (25% protein) but in which the operation of the urine concentrating mechanism was chronically stimulated by ADH infusion or by reduction in water intake.(ABSTRACT TRUNCATED AT 250 WORDS)