Plasma renin activity varies with the level of dietary protein, being higher on a high protein diet. To explore the molecular mechanisms underlying this relationship we first examined the effect of dietary protein on renin and angiotensinogen gene expression at the level of steady state mRNA in male Sprague-Dawley rats. Renal renin mRNA was higher on a 50% (high) compared to a 6% (low) protein diet both 3 d (9.4 +/- 1.1 vs. 5.3 +/- 0.4 pg/micrograms of total RNA; P less than 0.02) and 21 d (6.8 +/- 1.0 vs. 3.5 +/- 0.4 pg/micrograms of total RNA; P less than 0.02) after dietary change. No change occurred in either renal or liver angiotensinogen mRNA. When three levels of dietary protein were examined, renal renin mRNA was elevated on a 50% and lowered on a 6% protein diet compared to a more standard 20% protein diet. Kidney weights and renal protein, RNA, and RNA/DNA increased with the level of dietary protein reflecting protein-induced renal hypertrophy. Uninephrectomy resulted in no change in renin mRNA compared to sham operation (3.7 +/- 0.1 vs. 3.4 +/- 0.1 pg/micrograms RNA; P = NS) despite renal growth in the uninephrectomy group implicating dietary protein and not hypertrophy as the major factor for stimulating renin mRNA. In conclusion, the level of dietary protein is a novel and specific stimulus for changes in renal renin mRNA. The increased plasma renin activity on a high protein diet is due at least in part to increased renin synthesis.