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

Bernardo Rodríguez-Iturbe, Héctor Pons, Yasmir Quiroz, Katherine Gordon, Jaimar Rincón, Maribel Chávez, Gustavo Parra, Jaime Herrera-Acosta, Dulcenombre Gómez-Garre, Raquel Largo, Jesus Egido, Richard J. Johnson

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205 Scopus citations

Abstract

Background. Interstitial mononuclear cell infiltration is a feature of experimental models of salt-sensitive hypertension (SSHTN). Since several products of these cells are capable of modifying local vascular reactivity and sodium 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 subcutaneous minipumps. A high-sodium (4% NaCl) diet was started on the third week and was maintained until the eighth week. MMF (30 mg/kg, N = 15), an immunosuppressive drug, or vehicle (N = 15) was given daily by gastric gavage during the initial three weeks. Sham-operated rats (N = 9) were used as controls. Body weight, blood pressure (tail-cuff plethysmography), and serum creatinine were determined weekly. Urinary malondialdehyde (MDA) excretion, renal histology, and immunohistology, including the presence of Ang II and superoxide-producing cells, were analyzed at the end of Ang II infusion and at eight weeks. Results. MMF treatment did not modify hypertension induced during exogenous Ang II infusion, but prevented the subsequent SSHTN. Tubulointerstitial injury resulting from Ang II infusion was significantly reduced by MMF treatment, as were proliferative activity, T-cell infiltration and activation (interleukin-2 receptor expression), superoxide-producing cells, and urinary MDA excretion. Ang II-producing cells were present in the renal tubulointerstitium of rats with SSHTN (60 ± 30 Ang II-positive cells/mm2 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 II. The expression of Ang II receptors in the kidney was unmodified. Conclusions. SSHTN resulting from Ang II infusion is associated with infiltration and activation of immune cells that produce Ang II. MMF treatment reduces these features and prevents the development of SSHTN.

Original languageEnglish
Pages (from-to)2222-2232
Number of pages11
JournalKidney International
Volume59
Issue number6
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Blood pressure
  • Cell proliferation
  • Immune system
  • Immunosuppression
  • Mononuclear cell infiltrate
  • Rat experimental model
  • Renal interstitium

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