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Mycophenolate mofetil prevents salt-sensitive hypertension resulting from angiotensin II exposure
B Rodríguez-Iturbe1, H Pons, Y Quiroz
1Renal Service and Department of Immunobiology (INBIOMED), Hospital Universitario, Maracaibo, Venezuela. bri@iamnet.com
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/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 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.
Insights
Mycophenolate mofetil (MMF) prevents salt-sensitive hypertension (SSHTN) by reducing immune cell infiltration and angiotensin II (Ang II) production in the kidneys. This immunosuppressive drug treatment effectively blocks the development of SSHTN following Ang II infusion.
Area of Science:
- Nephrology
- Immunology
- Cardiovascular Research
Background:
- Interstitial mononuclear cell infiltration is a hallmark of experimental salt-sensitive hypertension (SSHTN).
- Immune cell products can influence vascular reactivity and sodium reabsorption.
- The immunosuppressive drug mycophenolate mofetil (MMF) inhibits immune cell infiltration and proliferation.
Purpose of the Study:
- To investigate the effect of MMF on angiotensin II (Ang II)-induced SSHTN in rats.
- To determine if MMF can modify the development of SSHTN.
Main Methods:
- Angiotensin II (Ang II) infusion in Sprague-Dawley rats for two weeks.
- High-sodium diet initiated and maintained for eight weeks.
- Daily administration of MMF (30 mg/kg) or vehicle during the first three weeks.
- Analysis of blood pressure, renal histology, immunohistology, and oxidative stress markers.
Main Results:
- MMF did not affect hypertension during initial Ang II infusion but prevented subsequent SSHTN.
- MMF significantly reduced tubulointerstitial injury, immune cell infiltration and activation, and oxidative stress.
- MMF treatment decreased the number of Ang II-producing cells in the renal tubulointerstitium.
Conclusions:
- Ang II-induced SSHTN involves immune cell infiltration and activation, with some lymphocytes producing Ang II.
- MMF effectively reduces these immune-related features and prevents the development of SSHTN.
- MMF represents a potential therapeutic strategy for managing SSHTN by targeting immune pathways.