Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass.
Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P < 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.
Diekmann
Fritz
F
Department of Nephrology and Renal Transplantation, Hospital Clínic, Villarroel, 170, E-08036 Barcelona, Spain. fdiekman@clinic.ub.es
Rovira
Jordi
J
Carreras
Joaquim
J
Arellano
Edgar M
EM
Bañón-Maneus
Elisenda
E
Ramírez-Bajo
María José
MJ
Gutiérrez-Dalmau
Alex
A
Brunet
Mercè
M
Campistol
Josep M
JM
D000818:Animals; D007166:Immunosuppressive Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011494:Protein Kinases / Q000187:drug effects*; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020123:Sirolimus / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism / Q000652:urine; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism