Rapamycin has dual opposing effects on proteinuric experimental nephropathies: is it a matter of podocyte damage?
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.
Torras
Juan
J
Laboratory of Experimental Nephrology, Department of Medicine, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain. 15268jta@comb.cat
Herrero-Fresneda
Immaculada
I
Gulias
Oscar
O
Flaquer
Maria
M
Vidal
August
A
Cruzado
Josep M
JM
Lloberas
Nuria
N
Franquesa
Marcel la
Ml
Grinyó
Josep M
JM
D000818:Animals; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009402:Nephrosis, Lipoid / Q000139:chemically induced / Q000188:drug therapy; D050199:Podocytes / Q000187:drug effects* / Q000502:physiology*; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D020123:Sirolimus