Mycophenolate mofetil prevents salt-sensitive hypertension resulting from angiotensin II exposure.
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.
Rodríguez-Iturbe
B
B
Renal Service and Department of Immunobiology (INBIOMED), Hospital Universitario, Maracaibo, Venezuela. bri@iamnet.com
Pons
H
H
Quiroz
Y
Y
Gordon
K
K
Rincón
J
J
Chávez
M
M
Parra
G
G
Herrera-Acosta
J
J
Gómez-Garre
D
D
Largo
R
R
Egido
J
J
Johnson
R J
RJ
D000804:Angiotensin II / Q000032:analysis / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002455:Cell Division / Q000502:physiology; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005353:Fibronectins / Q000032:analysis; D006977:Hypertension, Renal / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D007668:Kidney / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000652:urine; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D053495:Osteopontin; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000032:analysis; D012795:Sialoglycoproteins / Q000032:analysis; D013481:Superoxides / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000032:analysis / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005353:Fibronectins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D014662:Vasoconstrictor Agents; D053495:Osteopontin; D013481:Superoxides; D000804:Angiotensin II; D008315:Malondialdehyde; D003404:Creatinine; D009173:Mycophenolic Acid