Captopril enhances transforming growth factor (TGF)-beta1 expression in peripheral blood mononuclear cells: a mechanism independent from angiotensin converting enzyme inhibition? A study in cyclosporine-treated kidney-transplanted patients.
BACKGROUND
Angiotensin (Ang) II blockade has been shown to prevent the development of renal injury in immunologically mediated diseases, but the mechanism whereby it exerts its protective effect has not been clearly defined. Transforming growth factor (TGF)-beta1 is a multifunctional cytokine with a potent immunomodulatory activity that has the potential to counteract many of the pro-inflammatory effects apparently evoked by the activation of renin-angiotensin system (RAS) in immune cells.


METHODS
We set up an ex vivo and in vitro model to evaluate the effect of the angiotensin converting enzyme inhibitor (ACEi) captopril on the gene and protein expression of TGF-beta1 in human peripheral blood mononuclear cells (PBMC).


RESULTS
In 20 kidney transplant recipients chronically treated with cyclosporine (CsA), 1-month treatment with captopril increased TGF-beta mRNA by 120% and TGF-beta1 protein release by 140% upon stimulation of PBMC with phytohemagglutinin (PHA) and phorbol myristate acetate (PMA) ( P<0.01). PBMC from healthy controls, when exposed in vitro to 5 microM captopril, showed a significant increase of TGF-beta1 release, whereas the ACEi enalapril failed to modify the expression of the cytokine. Ang II (100 pM) strongly inhibited TGF-beta1 synthesis by PBMC, and such effect was completely abolished by the addition of 200 ng/mL CsA, as well as by 1 micrpM losartan. Thus, captopril enhances TGF-beta1 gene and protein expression by PBMC by way of a mechanism independent, at least in part, from ACE inhibition, while CsA abrogates the inhibition of TGF-beta1 expression induced by Ang II.


CONCLUSIONS
Collectively, these findings support the utility of combined treatment with captopril and CsA in the multitherapeutic management of organ transplant and, possibly, a strategy to decrease the dose of the calcineurin inhibitor in kidney-transplant recipients.
Di Paolo
Salvatore
S
Department of Emergency and Organ Transplant, Division of Nephrology, University of Bari, Bari, Italy. s.dipaolo@nephro.uniba.it.
Schena
Antonio
A
Stallone
Giovanni
G
Grandaliano
Giuseppe
G
Soccio
Michela
M
Cerullo
Giuseppina
G
Gesualdo
Loreto
L
Paolo Schena
Francesco
F
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000008:administration & dosage*; D016572:Cyclosporine / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D066298:In Vitro Techniques; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1
D000806:Angiotensin-Converting Enzyme Inhibitors; D007166:Immunosuppressive Agents; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D002216:Captopril; D007703:Peptidyl-Dipeptidase A