The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

Abstract

Mycophenolic acid (MPA) appears to have anti-fibrotic effects, but the molecular mechanisms underlying this are unknown. We prospectively studied 35 stable kidney transplant recipients maintained on cyclosporine and azathioprine. We converted 20 patients from azathioprine to enteric-coated mycophenolate sodium (EC-MPS) and continued the remaining 15 patients on azathioprine. Exploratory mRNA expression profiling, performed on five randomly selected EC-MPS patients, revealed significant upregulation of neutral endopeptidase (NEP), which is an enzyme that degrades angiotensin II. We confirmed these microarray data by measuring levels of NEP expression in all subjects; in addition, we found that NEP gene expression correlated inversely with proteinuria. In an additional 33 patients, glomerular and tubular NEP protein levels from renal graft biopsies were significantly higher among the 13 patients receiving cyclosporine ϩ EC-MPS than among the 12 patients receiving cyclosporine ϩ azathioprine or 8 patients receiving cyclosporine alone. Glomerular NEP expression inversely correlated with glomerulosclerosis and proteinuria, and tubular NEP expression inversely correlated with interstitial fibrosis. Incubation of human proximal tubular cells with MPA increased NEP gene expression in a doseand time-dependent manner. Moreover, MPA reduced angiotensin II-induced expression of the profibrotic factor plasminogen activator inhibitor-1, and a specific NEP inhibitor completely reversed this effect. Taken together, our data suggest that MPA directly induces expression of neutral endopeptidase, which may reduce proteinuria and slow the progression of renal damage in kidney transplant recipients. 21: 215721: -216821: , 201021: . doi: 10.1681 Over the last decade, the continuous progress in the development of immunosuppressive agents has enhanced both the efficacy and safety of antirejection regimens after renal transplantation, leading to a dramatic reduction in the incidence of acute rejection. 1 This significant improvement in short-term graft outcome was not followed by a similar advance in preventing graft loss caused by chronic graft injury. 2,3 The addition of mycophenolic acid (MPA) into contemporary immunosuppressive regimens represented an important step forward in the development of new therapeutic protocols in kidney transplantation. J Am Soc NephrolMPA exerts its immunosuppressive effect by inhibiting the inosine 5Ј monophosphate dehydro-

Randomized Trial of Three Induction Antibodies in Kidney Transplantation

“…Lastly, results of an ad hoc linear regression analysis of calculated CrCl suggest that the inferior long-term results observed in group B were specifically a result of early underimmunosuppression with TAC and MMF (but apparently not because of steroid avoidance). Two recent studies (13,14) show that early conversion from TAC to sirolimus does not result in improved glomerular filtration rate and less CAI, and another study (15) indicates that MMF offers protection against graft fibrosis, each supporting the results of our ad hoc analysis.…”

Effect of mycophenolate mofetil on progression of interstitial fibrosis and tubular atrophy after kidney transplantation: a retrospective study

“…Owing to the fact that there was no difference in incidence of acute rejection with respect to increased MMF exposure in our study, we believe that there may be a significant contribution of non-immune mechanisms in retardation of IF/TA in patients with higher MMF. In line with this, in many experimental models it has been shown that MMF has antiproliferative and antifibrotic effects 13 26 27. In the study of Jiang et al using rat renal ischaemia reperfusion injury, a time-dependent and dose-dependent correlation of higher MMF dose with better renal function and lower interstitial fibrosis was demonstrated.…”

“…Retrospective studies of renal recipients who were treated with MMF comparing azathioprin showed that MMF-treated patients had significantly less chronic allograft dysfunction 8 9. Besides being associated with lower acute rejection rates as compared to azathioprin,10 11 evidence from animal and human studies suggests that MMF may also exert direct antifibrotic properties due to its antiproliferative action on non-immune cells, including renal tubular cells and vascular smooth muscle cells 12 13…”

Long‐term efficacy and tolerability of mycophenolate mofetil therapy in diffuse scleroderma skin disease

“…5 It has also been demonstrated in vivo to down-regulate production of transforming growth factor beta, which is thought to result in reduced deposition of extracellular matrix and hence is a promising therapy in fibrotic disorders. 6 MMF has been associated with improvement in skin thickening in several observational studies in SSc, [7][8][9] and more recently, in the Scleroderma Lung Study II (SLS II). 10 This randomized controlled study compared the effect of CYC and MMF on forced vital capacity (FVC) in ILD in patients with diffuse or limited SSc.…”