title: A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease.
abstract: Autosomal-dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease, and no approved treatment is available in the United States to slow disease progression. The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in renal cysts, and while mTOR inhibitors are highly effective in rodent models, clinical trials in ADPKD have been disappointing due to dose-limiting extrarenal side effects. Since mTOR is known to be regulated by nutrients and cellular energy status, we hypothesized that dietary restriction may affect renal cyst growth. Here, we show that reduced food intake (RFI) by 23% profoundly affects polycystic kidneys in an orthologous mouse model of ADPKD with a mosaic conditional knockout of PKD1. This mild level of RFI does not affect normal body weight gain, cause malnutrition, or have any other apparent side effects. RFI substantially slows disease progression: relative kidney weight increase was 41 vs. 151% in controls, and proliferation of cyst-lining cells was 7.7 vs. 15.9% in controls. Mice on an RFI diet maintained kidney function and did not progress to end-stage renal disease. The two major branches of mTORC1 signaling, S6 and 4EBP1, are both suppressed in cyst-lining cells by RFI, suggesting that this dietary regimen may be more broadly effective than pharmacological mTOR inhibition with rapalogs, which primarily affects the S6 branch. These results indicate that polycystic kidneys are exquisitely sensitive to minor reductions in nutrient supply or energy status. This study suggests that a mild decrease in food intake represents a potential therapeutic intervention to slow disease progression in ADPKD patients.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, California.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kipp
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, California.
authors.forename: Mina
authors.initials: M
authors.lastname: Rezaei
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, California.
authors.forename: Louis
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, California.
authors.forename: Elyse C
authors.initials: EC
authors.lastname: Dewey
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, California weimbs@lifesci.ucsb.edu.
authors.forename: Thomas
authors.identifier: 0000-0001-9423-5561
authors.initials: T
authors.lastname: Weimbs
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D004195:Disease Models, Animal; D018450:Disease Progression; D004435:Eating / Q000502:physiology*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000178:diet therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; C546842:MTOR protein, human
keywords: ADPKD; food restriction; mTOR; polycystic kidney disease