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)-beta(1) 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-beta(1) 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(1) mRNA by 120% and TGF-beta(1), 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 μM captopril, showed a significant increase of TGF-β(1), release, whereas the ACEi enalapril failed to modify the expression of the cytokine. Ang II (100 μM) strongly inhibited TGF-β(1), synthesis by PBMC, and such effect was completely abolished by the addition of 200 ng/mL CsA, as well as by 1 μM losartan. Thus, captopril enhances TGF-β(1), 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-β(1), expression induced by Ang II. Conclusion. 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.