title: Mammalian target of rapamycin inhibition prevents glomerular hypertrophy in a model of renal mass reduction.
abstract: 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.
authors.affiliation: Department of Nephrology and Renal Transplantation, Laboratori Experimental de Nefrologia I Trasplantament, Hospital Clínic de Barcelona, Barcelona, Spain. jrovira1@clinic.ub.es
authors.forename: Jordi
authors.initials: J
authors.lastname: Rovira
authors.forename: Edgar M
authors.initials: EM
authors.lastname: Arellano
authors.forename: Joaquim
authors.initials: J
authors.lastname: Carreras
authors.forename: Begoña
authors.initials: B
authors.lastname: Campos
authors.forename: Barbara
authors.initials: B
authors.lastname: Vodenik
authors.forename: Elisenda
authors.initials: E
authors.lastname: Bañón-Maneus
authors.forename: María José
authors.initials: MJ
authors.lastname: Ramírez-Bajo
authors.forename: Daniel
authors.initials: D
authors.lastname: Moya-Rull
authors.forename: Amanda
authors.initials: A
authors.lastname: Solé-González
authors.forename: Astrid
authors.initials: A
authors.lastname: Hernández
authors.forename: Ignacio
authors.initials: I
authors.lastname: Revuelta
authors.forename: Luis F
authors.initials: LF
authors.lastname: Quintana
authors.forename: William J
authors.initials: WJ
authors.lastname: Howat
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campistol
authors.forename: Fritz
authors.initials: F
authors.lastname: Diekmann
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D003404:Creatinine; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus