title: Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease.
abstract: The disease-modifying effects of target of rapamycin complex 1 (TORC1) inhibitors during different stages of polycystic kidney disease (PKD) are not well defined. In this study, male Lewis Polycystic Kidney Disease (LPK) rats (a genetic ortholog of human NPHP9, phenotypically characterised by diffuse distal nephron cystic growth) and Lewis controls received either vehicle (V) or sirolimus (S, 0.2 mg/kg by intraperitoneal injection 5 days per week) during the early (postnatal weeks 3 to 10) or late stages of disease (weeks 10 to 20). In early-stage disease, sirolimus reduced kidney enlargement (by 63%), slowed the rate of increase in total kidney volume (TKV) in serial MRI by 78.2% (LPK+V: 132.3±59.7 vs. LPK+S: 28.8±12.0% per week) but only partly reduced the percentage renal cyst area (by 19%) and did not affect the decline in endogenous creatinine clearance (CrCl) in LPK rats. In late-stage disease, sirolimus reduced kidney enlargement (by 22%) and the rate of increase in TKV by 71.8% (LPK+V: 13.1±6.6 vs. LPK+S: 3.7±3.7% per week) but the percentage renal cyst area was unaltered, and the CrCl only marginally better. Sirolimus reduced renal TORC1 activation but not TORC2, NF-κB DNA binding activity, CCL2 or TNFα expression, and abnormalities in cilia ultrastructure, hypertension and cardiac disease were also not improved. Thus, the relative treatment efficacy of TORC1 inhibition on kidney enlargement was consistent at all disease stages, but the absolute effect was determined by the timing of drug initiation. Furthermore, cystic microarchitecture, renal function and cardiac disease remain abnormal with TORC1 inhibition, indicating that additional approaches to normalise cellular dedifferentiation, inflammation and hypertension are required to completely arrest the progression of PKDs.
authors.affiliation: Michael Stern Translational Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Michelle H T
authors.initials: MH
authors.lastname: Ta
authors.affiliation: Michael Stern Translational Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Kristina G
authors.initials: KG
authors.lastname: Schwensen
authors.affiliation: Department of Radiology, University of Sydney at Westmead Hospital, Sydney, Australia.|Faculty of Health Sciences, University of Sydney, Sydney, Australia.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Foster
authors.affiliation: Brain Dynamics Centre, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Mayuresh
authors.initials: M
authors.lastname: Korgaonkar
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.
authors.forename: Justyna E
authors.initials: JE
authors.lastname: Ozimek-Kulik
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Phillips
authors.affiliation: Department of Radiology, University of Sydney at Westmead Hospital, Sydney, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Peduto
authors.affiliation: Michael Stern Translational Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.|Department of Renal Medicine, Westmead Hospital, Western Sydney Local Heath District, Westmead, Sydney, Australia.
authors.forename: Gopala K
authors.initials: GK
authors.lastname: Rangan
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002923:Cilia / Q000648:ultrastructure; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000000981:diagnostic imaging / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D046912:Multiprotein Complexes; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus