W e have examined the possibility that changes in glomerular filtration rate (GFR) after changes in dietary protein intake may depend on altered function of the tubuloglomerular (TG) feedback system. We studied male Sprague-Dawley rats after dietary pretreatment for 9.6 +/- 3.6 (SD) d with isocaloric diets containing either 6% or 40% casein. We found that GFR in rats fed the high protein diet was 24-29% higher than in rats fed the low protein diet. Simultaneous measurements of single nephron GFR (SNGFR) in the distal tubule were 6.3 nl/min or 21% higher in the rats fed the high protein diet whereas proximally measured SNGFR was not statistically different in the two groups. The higher distally measured SNGFR of rats receiving the high protein diet was associated with a 4.2 nl/min or 50% smaller suppression of SNGFR by TG feedback (-4.3 vs. -8.5 nl/min, P less than 0.001). Loop perfusion experiments demonstrated that in rats fed the high protein diet the TG feedback mechanism was less sensitive than in rats fed the low protein diet. The TG feedback response in rats fed the low protein diet, as assessed by reductions in stop-flow pressure and SNGFR, was half-maximal at flows of 14-15 nl/min. In contrast, the TG feedback response in rats fed the high protein diet was half-maximal at 22-24 nl/min. Maximal suppression of stop-flow pressure and SNGFR and the slope of the TG feedback response to increasing loop flow rates were not different in the two groups. We conclude that the sensing mechanism of the TG feedback system is rendered less responsive by a high protein intake, and that this change permits GFR to increase.