Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats

Abstract

Activation of the mTOR pathway has been implicated in the mediation of the progression of polycystic kidney disease (PKD). Whereas targeted inhibition of mTOR has been proven to be effective in various animal models of autosomal dominant PKD, its efficacy in autosomal recessive PKD (ARPKD) remains to be elucidated. We examined the effects of sirolimus in PCK rats, an orthologous animal model of human ARPKD. Weaned PCK rats (n = 85) and SD-control rats (n = 72) received drinking water without and with sirolimus (corresponding to a daily intake of 2 mg/kg body weight) for 4, 8 and 12 weeks, respectively. The renal and hepatic functions were monitored throughout the treatment periods. Kidneys and livers were harvested and investigated with respect to progression of fibrosis, and number and size of cysts using the QWin image analysis programme. Expression of Akt, mTOR and its downstream target pS6K were assessed by immunohistochemistry. Five out of 43 sirolimus-treated PCK rats, but none of the controls, died during the study. Sirolimus treatment resulted in slightly reduced weight gain. In PCK rats, grossly enlarged kidney and livers as well as hepatic fibrosis together with enlarged bile ducts were readily detectable. Whereas activation of Akt/mTOR signalling was hardly detectable in the kidneys of SD rats, strong signals were seen in the kidneys of PCK rats. Despite a significantly reduced relative kidney weight after 12 weeks of treatment (P < 0.05), neither fibrosis and cyst area nor renal function improved during treatment. Sirolimus-treated PCK rats showed only a minor inhibition of renal mTOR-specific phosphorylation of S6K. Male PCK rats on sirolimus presented with increased concentrations of bile acids and bilirubin compared with controls (each P < 0.05 at 12 weeks). Similar, albeit non-significant, effects were noted in female PCK rats. Sirolimus failed to attenuate progression of kidney and liver disease in PCK rats. The lack of a protective effect might be due to intrinsic or acquired rapamycin resistance in this animal model of ARPKD.