Mycophenolate mofetil prevents salt-sensitive hypertension resulting from angiotensin II exposure

Background. Interstitial mononuclear cell infiltration is a feature of expe rimental models of salt-sensitive hypertension (SSHTN). Since several produ cts of these cells are capable of modifying local vascular reactivity and s odium reabsorption, we investigated whether mycophenolate mofetil (MMF), a drug known to inhibit infiltration and proliferation of immune cells, would modify the SSHTN induced by angiotensin II (Ang II) infusion. Methods. Sprague-Dawley rats received Ang II for two weeks using subcutaneo us minipumps. A high-sodium (4% NaCl) diet was started on the third week an d was maintained until the eighth week. MMF (30 mg/kg, N = 15), an immunosu ppressive drug, or vehicle (N = 15) was given daily by gastric gavage durin g the initial three weeks. Sham-operated rats (N = 9) were used as controls . Body weight, blood pressure (tail-cuff plethysmography), and serum creati nine were determined weekly. Urinary malondialdehyde (MDA) excretion, renal histology, and immunohistology, including the presence of Ang II and super oxide-producing cells, were analyzed at the end of Ang II infusion and at e ight weeks. Results. MMF treatment did not modify hypertension induced during exogenous Ang II infusion, but prevented the subsequent SSHTN. Tubulointerstitial in jury resulting from Ang II infusion was significantly reduced by MMF treatm ent, as were proliferative activity, T-cell infiltration and activation (in terleukin-2 receptor expression), superoxide-producing cells, and urinary M DA excretion. Ang II-producing cells were present in the renal tubulointers titium of rats with SSHTN (60 +/- 30 Ang II-positive cells/mm(2) at 8 weeks ) and were reduced by two thirds in the MMF-treated group. Forty percent of lymphocytes infiltrating the tubulointerstitium stained positive for Ang I I. The expression of Ang II receptors in the kidney was unmodified. Conclusions. SSHTN resulting from Ang II infusion is associated with infilt ration and activation of immune cells that produce Ang II. MMF treatment re duces these features and prevents the development of SSHTN.