Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease.
OBJECTIVE
Rapamycin inhibits cyst growth in polycystic kidney disease by targeting the mammalian target of rapamycin (mTOR). To determine if this is a class effect of the mTOR inhibitors, we examined the effect of everolimus, the analogue of rapamycin, on disease progression in the Han:SPRD rat model of polycystic kidney disease.


METHODS
Four-week-old male heterozygous cystic (Cy/+) and wild-type normal (+/+) Han:SPRD rats were administered everolimus or vehicle (3 mg/kg/day) by gavage for 5 weeks. Kidney function and whole-blood trough levels of everolimus were monitored. After treatment kidney weight and cyst volume density were assessed. Tubule epithelial cell proliferation was assessed by BrdU staining.


RESULTS
Everolimus trough levels between 5 and 7 microg/l were sufficient to significantly reduce kidney and cyst volume density by approximately 50 and 40%, respectively. The steady decrease of kidney function in Cy/+ rats was reduced by 30% compared with vehicle-treated Cy/+ rats. Everolimus treatment markedly reduced the number of 5-bromo-2-deoxyuridine-labeled nuclei in cyst epithelia. Body weight gain and kidney function were impaired in everolimus-treated wild-type rats.


CONCLUSIONS
Moderate dosage of everolimus inhibits cystogenesis in Han:SPRD rats. The inhibitory effect of everolimus appears to represent a class effect of mTOR inhibitors.
Wu
Ming
M
Physiological Institute , University Zürich Irchel, Zürich, Switzerland.
Wahl
Patricia R
PR
Le Hir
Michel
M
Wackerle-Men
Ying
Y
Wuthrich
Rudolf P
RP
Serra
Andreas L
AL
D000818:Animals; D003560:Cysts / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D000068338:Everolimus; D007677:Kidney Function Tests / Q000379:methods; D008297:Male; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D011922:Rats, Mutant Strains; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000068338:Everolimus; D020123:Sirolimus