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NDT Advance Access published online on August 11, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp367
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Rapamycin has dual opposing effects on proteinuric experimental nephropathies: is it a matter of podocyte damage?

Juan Torras1, Immaculada Herrero-Fresneda1, Oscar Gulias1, Maria Flaquer1, August Vidal2, Josep M. Cruzado1, Nuria Lloberas1, Marcel·la Franquesa1 and Josep M. Grinyó1

1 Laboratory of Experimental Nephrology, Department of Medicine, Hospital Universitari de Bellvitge 2 Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain

Correspondence and offprint requests to: Juan Torras; E-mail: 15268jta{at}comb.cat



  Abstract

Background. In clinical renal transplantation, an increase in proteinuria after conversion from calcineurin inhibitors to rapamycin has been reported. In contrast, there are studies showing a nephro-protective effect of rapamycin in proteinuric diseases characterized by progressive interstitial inflammatory fibrosis.

Methods. Because of the contradictory reports concerning rapamycin on proteinuria, we examined proteinuria and podocyte damage markers on two renal disease models, with clearly different pathophysiological mechanisms: a glomerular toxico-immunological model induced by puromycin aminonucleoside, and a chronic hyperfiltration and inflammatory model by mass reduction, both treated with a fixed high rapamycin dose.

Results. In puromycin groups, rapamycin provoked significant increases in proteinuria, together with a significant fall in podocin immunofluorescence, as well as clear additional damage to podocyte foot processes. Conversely, after mass reduction, rapamycin produced lower levels of proteinuria and amelioration of inflammatory and pro-fibrotic damage. In contrast to the puromycin model, higher glomerular podocin and nephrin expression and amelioration of glomerular ultrastructural damage were found.

Conclusions. We conclude that rapamycin has dual opposing effects on subjacent renal lesion, with proteinuria and podocyte damage aggravation in the glomerular model and a nephro-protective effect in the chronic inflammatory tubulointerstitial model. Rapamycin produces slight alterations in podocyte structure when acting on healthy podocytes, but it clearly worsens those podocytes damaged by other concomitant injury.

Keywords: proteinuria; puromycin aminonucleoside nephropathy; rapamycin; renal mass reduction

Received for publication: 4.12.08
Accepted in revised form: 1. 7.09


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