title: Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1.
abstract: Aberrant activation of the mammalian target of rapamycin (mTOR) pathway occurs in polycystic kidney disease (PKD). mTOR inhibitors, such as rapamycin, are highly effective in several rodent models of PKD, but these models result from mutations in genes other than Pkd1 and Pkd2, which are the primary genes responsible for human autosomal dominant PKD. To address this limitation, we tested the efficacy of rapamycin in a mouse model that results from conditional inactivation of Pkd1. Mosaic deletion of Pkd1 resulted in PKD and replicated characteristic features of human PKD including aberrant mTOR activation, epithelial proliferation and apoptosis, and progressive fibrosis. Treatment with rapamycin was highly effective: It reduced cyst growth, preserved renal function, inhibited epithelial cell proliferation, increased apoptosis of cyst-lining cells, and inhibited fibrosis. These data provide in vivo evidence that rapamycin is effective in a human-orthologous mouse model of PKD.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106-9610, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Shillingford
authors.forename: Klaus B
authors.initials: KB
authors.lastname: Piontek
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Germino
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimbs
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001806:Blood Urea Nitrogen; D002455:Cell Division / Q000502:physiology; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000473:pathology / Q000503:physiopathology; D007686:Kidney Tubules, Distal / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009030:Mosaicism; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D007381:Intermediate Filament Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; C577484:NES protein, human; C577485:Nes protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse