A mild reduction of food intake slows disease progression in an 1 orthologous mouse model of polycystic kidney disease

14 15 Autosomal-dominant polycystic kidney disease is a common cause of end-stage renal 16 disease, and no approved treatment is available in the US to slow disease progression. 17 The mTOR signaling pathway is aberrantly activated in renal cysts, and, while mTOR 18 inhibitors are highly effective in rodent models, clinical trials in ADPKD have been 19 disappointing due to dose-limiting extra-renal side effects. Since mTOR is known to be 20 regulated by nutrients and cellular energy status we hypothesized that dietary restriction 21 may affect renal cyst growth. Here we show that reduced food intake (RFI) by 23% 22 profoundly affects polycystic kidneys in an orthologous mouse model of ADPKD with a 23 mosaic conditional knockout of PKD1. This mild level of RFI does not affect normal 24 body weight gain, cause malnutrition or any other apparent side effects. RFI 25 substantially slows disease progression: relative kidney weight increase was 41% vs. 26 151% in controls, proliferation of cyst-lining cells was 7.7% vs. 15.9% in controls. Mice 27 on RFI diet maintained kidney function and did not progress to end-stage renal disease. 28 The two major branches of mTORC1 signaling, S6 and 4EBP1, are both suppressed in 29 cyst-lining cells by RFI suggesting that this dietary regimen may be more broadly 30 effective than pharmacological mTOR inhibition with rapalogues which primarily affects 31 the S6 branch. These results indicate that polycystic kidneys are exquisitely sensitive to 32 minor reductions in nutrient supply or energy status. This study suggests that a mild 33 decrease in food intake represents a potential therapeutic intervention to slow disease 34 progression in ADPKD patients. 35