BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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 PCKrats, an orthologous animal model of humanARPKD. METHODS: Weaned PCKrats (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. RESULTS: Five out of 43 sirolimus-treated PCKrats, but none of the controls, died during the study. Sirolimus treatment resulted in slightly reduced weight gain. In PCKrats, 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 PCKrats. 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 PCKrats showed only a minor inhibition of renal mTOR-specific phosphorylation of S6K. Male PCKrats 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 PCKrats. CONCLUSIONS:Sirolimus failed to attenuate progression of kidney and liver disease in PCKrats. The lack of a protective effect might be due to intrinsic or acquired rapamycin resistance in this animal model of ARPKD.
Authors: Jacob A Torres; Mina Rezaei; Caroline Broderick; Louis Lin; Xiaofang Wang; Bernd Hoppe; Benjamin D Cowley; Vincenzo Savica; Vicente E Torres; Saeed Khan; Ross P Holmes; Michal Mrug; Thomas Weimbs Journal: J Clin Invest Date: 2019-07-30 Impact factor: 14.808
Authors: Kameswaran Ravichandran; Iram Zafar; Zhibin He; R Brian Doctor; Radu Moldovan; Adam E Mullick; Charles L Edelstein Journal: Hum Mol Genet Date: 2014-05-08 Impact factor: 6.150
Authors: Maria J Perugorria; Tatyana V Masyuk; Jose J Marin; Marco Marzioni; Luis Bujanda; Nicholas F LaRusso; Jesus M Banales Journal: Nat Rev Gastroenterol Hepatol Date: 2014-09-30 Impact factor: 46.802