Cyclosporine (CsA) is among the most widely used immunosuppressants for preventing graft rejection and autoimmune diseases. However, its clinical use is hampered by its significant nephrotoxicity and effects as a cause of hypertension. The proximal tubular Na+-H+ exchanger (NHE3) is responsible for transcellular reabsorption of 30%-60% of the sodium filtered by the glomerulus. CsA induces a reduction of absolute sodium reabsorption, and this effect is, most probably, correlated with the decrease of NHE3 activity. In Henle's loop, in physiological conditions, the Na+-K+-2Cl- cotransporter (NKCC2) reabsorbs approximately 20% of the filtered Na+ and Cl-. CsA increases the NKCC2 activity in cultured bovine renal NBL-1 cells. In the collecting duct, CsA may cause hypertension by stimulating the epithelial Na+ channel (ENaC) through a pathway associated with inhibition of ABCA1 and consequent elevation of cholesterol in the cells. It is still unclear whether CsA regulates the Na+-Cl- cotransporter in the distal tubule and ENaC in the collecting duct. Aside from this, there is evidence suggesting the possible involvement of free radicals during the development of CsA-induced hypertension. The hypertensive effect is, most probably, correlated with higher levels of superoxide (O2-) that decreases glomerular filtration rate and may affect fluid reabsorption along the nephron.