The present study evaluated the influence and mechanism of action of dietary protein intake in Dahl SS hypertension and renal disease. Rats were fed isocaloric diets with low (6%), normal (18%), or high (30%) amounts of protein and 0.4% NaCl from 5 to 12 weeks of age; the NaCl content of the diets was then increased to 4.0% NaCl from 12 to 15 weeks of age. Rats fed the high-protein diet developed the highest mean arterial blood pressure and urine albumin-to-creatinine ratio when fed the 4.0% NaCl diet (153±7 mm Hg and 8.0±2.4, respectively) compared to rats fed normal protein (132±3 mm Hg, 1.2±0.3) or low-protein (132±6 mm Hg, 0.3±0.1) diets. Significantly greater numbers of infiltrating T lymphocytes were observed in kidneys of SS rats fed the high-protein diet (18.9±3×10 cells) than in rats fed the low-protein diet (9.1±3×10 cells). Furthermore, treatment of SS rats fed the high-protein diet with the immunosuppressant agent mycophenolate mofetil (20 mg/kg per day, ip) significantly reduced the number of infiltrating T cells in the kidneys (from 18.9±2.7 to 10.6±2.0×10 cells) while decreasing blood pressure (from 133±3 to 113±4 mm Hg) and the albumin/creatinine ratio (from 10.9±2.3 to 5.4±1.2). These results demonstrate that restriction of protein intake protects the Dahl SS rats from hypertension and kidney disease and indicates that infiltrating immune cells play a pathological role in Dahl SS rats fed a high-protein diet. Moreover, the results show that hypertension in Dahl SS rats is sensitive to both NaCl and protein intake. © 2011 American Heart Association. All rights reserved.