A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease

American Journal of Physiology. Renal Physiology
Kevin R KippThomas Weimbs

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 c...Continue Reading

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Citations

Nov 8, 2018·The British Journal of Nutrition·Si-Yang WangXiang-Mei Chen
Aug 6, 2016·Journal of the American Society of Nephrology : JASN·Wouter N LeonhardDorien J M Peters
Jul 28, 2018·Clinical Journal of the American Society of Nephrology : CJASN·Fouad T Chebib, Vicente E Torres
Nov 10, 2017·Journal of the American Society of Nephrology : JASN·Kristen L NowakMichel Chonchol
May 28, 2019·Clinical and Experimental Nephrology·Ismail KocyigitJonas Axelsson
May 3, 2018·American Journal of Physiology. Renal Physiology·Kevin R KippThomas Weimbs
Dec 26, 2018·Clinical Kidney Journal·Roman-Ulrich Müller, Thomas Benzing
Sep 8, 2017·American Journal of Physiology. Renal Physiology·Taketsugu HamaHiroyuki Suzuki
Aug 19, 2018·Nature Reviews. Nephrology·Valeria PadovanoMichael J Caplan
Nov 27, 2019·Expert Reviews in Molecular Medicine·Jennifer Q J ZhangGopala K Rangan
Mar 8, 2018·American Journal of Physiology. Renal Physiology·Erin E OlsanThomas Weimbs
Dec 20, 2019·Journal of Nephrology·Francesca Testa, Riccardo Magistroni
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Jul 25, 2019·Nutrients·Sol CarriazoMaria Dolores Sanchez-Niño
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Dec 28, 2019·Cellular Signalling·Kristen L Nowak, Charles L Edelstein
Jul 16, 2021·Current Opinion in Nephrology and Hypertension·Esther Meijer, Ron T Gansevoort

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