This study explored the hypothesis that dietary salt promoted changes in renal expression of TGF-beta1 and NOS3 by modulating the mitogen-activated protein kinase (MAPK) pathways. Sprague-Dawley rats were maintained for four days on formulated diets that contained 0.3, 1.0, 3.0, or 8.0% NaCl. An increase in salt intake to greater than or equal to 3.0% NaCl increased kinase activities of p38 MAPK and p42/44 MAPK, but not p46/54 JNK/SAPK, in the cortex and outer and inner medulla. Associated with this increased activity was a relative increase in the phosphorylated forms of the transcription factors ATF-2 and Elk-1. Compared with rats on 0.3% NaCl diet, glomerular preparations from rats on 8.0% NaCl diet contained more NOS3 and produced greater amounts of total and active TGF-beta1 and NOx. PD-098059, a MEK1 inhibitor, and SB-203580, an inhibitor of p38 MAPKalpha-gamma, diminished NOS3 expression and production of TGF-beta1 and NOx. TEA, administered intravenously 5 min before harvesting kidneys of rats on the 8.0% NaCl diet, decreased activities of both p38 MAPK and p42/44 MAPK, compared with vehicle-treated animals. Thus, an increase in dietary salt activated through a TEA-sensitive pathway the p38 MAPK and p42/44 MAPK signaling cascades, which promoted the increase in glomerular TGF-beta1 and NOS3 expression.