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.

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.