RGD Reference Report - Rapamycin inhibits PAI-1 expression and reduces interstitial fibrosis and glomerulosclerosis in chronic allograft nephropathy. - Rat Genome Database

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Rapamycin inhibits PAI-1 expression and reduces interstitial fibrosis and glomerulosclerosis in chronic allograft nephropathy.

Authors: Pontrelli, Paola  Rossini, Michele  Infante, Barbara  Stallone, Giovanni  Schena, Antonio  Loverre, Antonia  Ursi, Michele  Verrienti, Raffaella  Maiorano, Annamaria  Zaza, Gianluigi  Ranieri, Elena  Gesualdo, Loreto  Ditonno, Pasquale  Bettocchi, Carlo  Schena, Francesco Paolo  Grandaliano, Giuseppe 
Citation: Pontrelli P, etal., Transplantation. 2008 Jan 15;85(1):125-34. doi: 10.1097/01.tp.0000296831.91303.9a.
RGD ID: 13208601
Pubmed: PMID:18192922   (View Abstract at PubMed)
DOI: DOI:10.1097/01.tp.0000296831.91303.9a   (Journal Full-text)


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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SERPINE1HumanChronic Allograft Nephropathy treatmentIMP  RGD 
Serpine1RatChronic Allograft Nephropathy treatmentISOSERPINE1 (Homo sapiens) RGD 
Serpine1MouseChronic Allograft Nephropathy treatmentISOSERPINE1 (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Serpine1  (serpin family E member 1)

Genes (Mus musculus)
Serpine1  (serine (or cysteine) peptidase inhibitor, clade E, member 1)

Genes (Homo sapiens)
SERPINE1  (serpin family E member 1)


Additional Information