Mycophenolate mofetil prevents salt-sensitive hypertension resulting from nitric oxide synthesis inhibition

Recent studies have suggested that subtle microvascular and tubulointerstit ial injury in the kidney can cause salt-sensitive hypertension. To test thi s hypothesis, we determined whether the mild renal disease induced by trans ient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministratio n of the immunosuppressive agent mycophenolate mofetil (MMF) would block th e development of salt sensitivity. N-omega-nitro-L-arginine-methyl ester (L -NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rat s with or without MMF (30 mg.kg(-1).day(-1) by gastric gavage), followed by a 1-wk "washout" period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measure d serially. L-NAME treatment resulted in acute hypertension and the develop ment of mild renal injury. During the washout period, blood pressure return ed to normal, only to return to the hypertensive range on exposure of the a nimals to a high-salt diet. MMF treatment prevented the development of hype rtension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the devel opment of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.