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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Physiol+Renal+Physiol
2016 ; 310
(8
): F726-F731
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A mild reduction of food intake slows disease progression in an orthologous mouse
model of polycystic kidney disease
#MMPMID26764208
Kipp KR
; Rezaei M
; Lin L
; Dewey EC
; Weimbs T
Am J Physiol Renal Physiol
2016[Apr]; 310
(8
): F726-F731
PMID26764208
show ga
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.