title: Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model.
abstract: BACKGROUND
  The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFβ expression in the 5/6 nephrectomy model in Wistar rats.
  
  
  METHODS
  This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation.
  
  
  RESULTS
  Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFβ observed in the remnant kidney model.
  
  
  CONCLUSIONS
  Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFβ mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin.
authors.affiliation: Centro de Nefrología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Melania
authors.initials: M
authors.lastname: Kurdián
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Herrero-Fresneda
authors.forename: Nuria
authors.initials: N
authors.lastname: Lloberas
authors.forename: Pepita
authors.initials: P
authors.lastname: Gimenez-Bonafe
authors.forename: Virginia
authors.initials: V
authors.lastname: Coria
authors.forename: María T
authors.initials: MT
authors.lastname: Grande
authors.forename: José
authors.initials: J
authors.lastname: Boggia
authors.forename: Leonel
authors.initials: L
authors.lastname: Malacrida
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Arévalo
authors.forename: Francisco
authors.initials: F
authors.lastname: González-Martínez
authors.forename: José M
authors.initials: JM
authors.lastname: López-Novoa
authors.forename: Josep
authors.initials: J
authors.lastname: Grinyó
authors.forename: Oscar
authors.initials: O
authors.lastname: Noboa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000097:blood / Q000652:urine; D000068338:Everolimus; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects*; D009392:Nephrectomy / Q000009:adverse effects*; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013053:Spectrophotometry; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D000068338:Everolimus; D003404:Creatinine; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus