Rapamycin inhibits PAI-1 expression and reduces interstitial fibrosis and glomerulosclerosis in chronic allograft nephropathy.
BACKGROUND
Chronic allograft nephropathy (CAN) is characterized by deposition of extracellular matrix (ECM) in all renal compartments. PAI-1 seems to play a pivotal role in ECM turnover in CAN. Rapamycin has been shown to improve long-term graft survival in patients with CAN. The aim of the study was to evaluate the molecular mechanisms underlying the beneficial effects of rapamycin on CAN progression at glomerular and tubulointerstitial level.


METHODS
After a biopsy-proven CAN diagnosis (T0), 18 patients on calcineurin inhibitors (CNI) were randomly assigned in a 2:1 ratio to continue CNI (6 patients) or to receive rapamycin (RAPA; 12 patients). After 2 years of treatment (T24), all patients underwent a second renal biopsy. Morphometric analysis was conducted at T0 and at T24. PAI-1 expression was evaluated at T0 and T24 by immunohistochemistry. We evaluated the effect of rapamycin on PAI-1 gene expression in cultured proximal tubular cells incubated with CD40L or thrombin, two potential CAN pathogenic mediators.


RESULTS
The RAPA group showed a significant regression of glomerulosclerotic lesions and only a 26% increase in interstitial fibrosis after 2 years compared to baseline, whereas the CNI group showed progression of glomerulosclerosis and 112% increase in fibrosis. Glomerular and tubulointerstitial PAI-1 expression was reduced compared to the baseline in the RAPA group, while they were unchanged in the CNI group. In vitro data showed that rapamycin significantly reduced PAI-1 gene expression induced by both CD40L and thrombin in proximal tubular epithelial cells.


CONCLUSIONS
These data suggest that rapamycin may modulate ECM deposition in CAN reducing PAI-1 expression.
Pontrelli
Paola
P
Division of Nephrology, Department of Biomedical Sciences, University of Foggia, Foggia, Italy.
Rossini
Michele
M
Infante
Barbara
B
Stallone
Giovanni
G
Schena
Antonio
A
Loverre
Antonia
A
Ursi
Michele
M
Verrienti
Raffaella
R
Maiorano
Annamaria
A
Zaza
Gianluigi
G
Ranieri
Elena
E
Gesualdo
Loreto
L
Ditonno
Pasquale
P
Bettocchi
Carlo
C
Schena
Francesco Paolo
FP
Grandaliano
Giuseppe
G
D000328:Adult; D001706:Biopsy; D023201:CD40 Ligand / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D018450:Disease Progression; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D012598:Sclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020123:Sirolimus / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; D023201:CD40 Ligand; D013917:Thrombin; D020123:Sirolimus