Regulation of sodium transporters in the kidney during cyclosporine treatment

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.