Mammalian target of rapamycin inhibition prevents glomerular hypertrophy in a model of renal mass reduction.
BACKGROUND
Sirolimus (SRL) is a potent and specific immunosuppressive drug used in organ transplantation, as basic therapy or in combination with calcineurin inhibitors. Although SRL is a nonnephrotoxic drug, many reports have related its use with the development of proteinuria, especially after conversion. Therefore, the aim of this study was to elucidate the interrelation between early and late SRL administration on the development of glomerular hypertrophy and proteinuria in a model of renal mass reduction (RMR).


METHODS
Rats underwent 2/3 cryoablation of the left kidney and subsequent right nephrectomy (n=42) or sham operations (n=29). Two weeks before (early study) or 12 weeks after (late study) surgery, SRL or vehicle was administered three times weekly. Creatinine clearance and proteinuria were determined throughout the study, and a complete histologic analysis was performed at the end of the study.


RESULTS
Treatment with SRL had no effect on creatinine clearance, independently of the administration time. Four weeks after RMR, a significant increase in proteinuria was observed. Proteinuria was stabilized after early and late SRL administration, whereas vehicle-treated animals showed a further increase in proteinuria. Glomerular hypertrophy was strongly associated with proteinuria, and early SRL introduction prevented glomerular enlargement. The histologic analysis showed less structural damage in the two groups of animals treated with SRL than in the control group.


CONCLUSIONS
Although early SRL introduction blocked glomerular hypertrophy, SRL treatment revealed the potential to halt progression of proteinuria and histologic damage at any time of administration in a model of RMR.
Rovira
Jordi
J
Department of Nephrology and Renal Transplantation, Laboratori Experimental de Nefrologia I Trasplantament, Hospital Clínic de Barcelona, Barcelona, Spain. jrovira1@clinic.ub.es
Arellano
Edgar M
EM
Carreras
Joaquim
J
Campos
Begoña
B
Vodenik
Barbara
B
Bañón-Maneus
Elisenda
E
Ramírez-Bajo
María José
MJ
Moya-Rull
Daniel
D
Solé-González
Amanda
A
Hernández
Astrid
A
Revuelta
Ignacio
I
Quintana
Luis F
LF
Howat
William J
WJ
Campistol
Josep M
JM
Diekmann
Fritz
F
D000818:Animals; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006984:Hypertrophy / Q000473:pathology* / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism / Q000628:therapy*; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D011507:Proteinuria; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D007166:Immunosuppressive Agents; D003404:Creatinine; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus