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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 Nephrology+(Carlton)
2012 ; 17
(8
): 739-47
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Rapamycin-mediated suppression of renal cyst expansion in del34 Pkd1-/- mutant
mouse embryos: an investigation of the feasibility of renal cyst prevention in
the foetus
#MMPMID22725947
Stayner C
; Shields J
; Slobbe L
; Shillingford JM
; Weimbs T
; Eccles MR
Nephrology (Carlton)
2012[Nov]; 17
(8
): 739-47
PMID22725947
show ga
AIM: Polycystic kidney disease (PKD) in humans involves kidney cyst expansion
beginning in utero. Recessive PKD can result in end-stage renal disease (ESRD)
within the first decade, whereas autosomal dominant PKD (ADPKD), caused by
mutations in the PKD1 or PKD2 gene, typically leads to ESRD by the fifth decade
of life. Inhibition of mTOR signalling was recently found to halt cyst formation
in adult ADPKD mice. In contrast, no studies have investigated potential
treatments to prevent cyst formation in utero in recessive PKD. Given that
homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to
investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in
foetal Pkd1 homozygous mutant mice. METHODS: Pregnant Pkd1(+/-) female mice
(mated with Pkd1(+/-) male mice) were treated with rapamycin from E14.5 to E17.5.
Foetal kidneys were dissected, genotyped and evaluated by cyst size as well as
expression of the developmental marker, Pax2. RESULTS: Numerous cysts were
present in Pkd1(-/-) kidneys, which were twice the weight of wild-type kidneys.
Cyst size was reduced by a third in rapamycin-treated Pkd1(-/-) kidney sections
and kidney mass was reduced to near wild-type levels. However, total cyst number
was not reduced compared with control embryos. Pax2 expression and kidney
development were unaltered in rapamycin-treated mice but some lethality was
observed in Pkd1(-/-) null embryos. CONCLUSION: Rapamycin treatment reduces cyst
formation in Pkd1(-/-) mutant mice; therefore, the prevention of kidney cyst
expansion in utero by mTOR inhibition is feasible. However, selective
rapamycin-associated lethality limits its usefulness as a treatment in utero.