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For chronic nephrotoxicity, rats fed with low-sodium diet were divided into groups receiving vehicle, spironolactone (Sp), CsA, and CsA+Sp, for 21 days. Creatinine clearance, survival percentage, and renocortical mRNA levels of pro-renin, angiotensinogen (Ang), angiotensin receptors (AT<jats:sub>1A<\/jats:sub>, AT<jats:sub>1B<\/jats:sub>, and AT<jats:sub>2<\/jats:sub>), preproendothelin, endothelin receptors (ET<jats:sub>A<\/jats:sub>, ET<jats:sub>B<\/jats:sub>), cyclooxygenase-2 (COX-2), and adenosine receptors (Ad<jats:sub>1<\/jats:sub>, Ad<jats:sub>2A<\/jats:sub>, Ad<jats:sub>2B<\/jats:sub>, and Ad<jats:sub>3<\/jats:sub>) were analyzed. For acute nephrotoxicity, similar groups fed with a standard chow diet for 7 days were included. Serum potassium and sodium, glomerular filtration rate (GFR), and renal blood flow (RBF) were determined. In chronic model, CsA produced pro-renin and ET upregulation, altered adenosine receptors expression, and reduced Ang, AT<jats:sub>1A<\/jats:sub>, AT<jats:sub>1B<\/jats:sub>, ET<jats:sub>B<\/jats:sub>, and COX-2 mRNA levels. Spironolactone protective effect in chronic nephrotoxicity was associated with prevention of pro-renin upregulation and increased AT<jats:sub>2<\/jats:sub>, together with ET<jats:sub>B<\/jats:sub>reduction. In acute nephrotoxicity, spironolactone completely prevented GFR and RBF reduction induced by CsA. Our results suggest that aldosterone contributes to renal vasoconstriction observed in CsA nephrotoxicity and that renoprotection conferred by spironolactone was related to modification of renocortical vasoactive pathways expression, in which pro-renin normalization was the most evident change in chronic nephropathy. 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