An mTOR kinase inhibitor slows disease progression in a rat model of polycystic kidney disease.

نویسندگان

  • Kameswaran Ravichandran
  • Iram Zafar
  • Abdullah Ozkok
  • Charles L Edelstein
چکیده

BACKGROUND The mTOR pathway, which consists of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), is activated in polycystic kidney disease (PKD) kidneys. Sirolimus and everolimus indirectly bind and inhibit mTORC1. A novel group of drugs, the mTOR kinase inhibitors, directly bind to mTOR kinase, thus inhibiting both mTORC1 and 2. The aim of the study was to determine the therapeutic effect of an mTOR kinase inhibitor, PP242, in the Han:SPRD rat (Cy/+) model of PKD. METHODS Male rats were treated with PP242 5 mg/kg/day IP or vehicle for 5 weeks. RESULTS PP242 significantly reduced the kidney enlargement, the cyst density and the blood urea nitrogen in Cy/+ rats. On immunoblot of kidneys, PP242 resulted in a decrease in pS6, a marker of mTORC1 signaling and pAkt(Ser473), a marker of mTORC2 signaling. mTORC plays an important role in regulating cytokine production. There was an increase in IL-1, IL-6, CXCL1 and TNF-α in Cy/+ rat kidneys that was unaffected by PP242. Apoptosis or proliferation is known to play a causal role in cyst growth. PP242 had no effect on caspase-3 activity, TUNEL positive or active caspase-3-positive tubular cells in Cy/+ kidneys. PP242 reduced the number of proliferating cells per cyst and per non-cystic tubule in Cy/+ rats. CONCLUSIONS In a rat model of autosomal dominant polycystic kidney disease, PP242 treatment (i) decreases proliferation in cystic and non-cystic tubules; (ii) inhibits renal enlargement and cystogenesis and (iii) significantly reduces the loss of kidney function.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Mannose-binding lectin and the kidney.

et al. Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease. Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease. Magenheimer BS et al. Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching ce...

متن کامل

Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD).

BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is characterized by dysregulated tubular epithelial cell growth, resulting in the formation of multiple renal cysts and progressive renal failure. To date, there is no effective treatment for ADPKD. The mammalian target of rapamycin (mTOR) is an atypical protein kinase and a central controller of cell growth and proliferation. We e...

متن کامل

A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease.

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 disappoint...

متن کامل

A mild reduction of food intake slows disease progression in an 1 orthologous mouse model of polycystic kidney disease

14 15 Autosomal-dominant polycystic kidney disease is a common cause of end-stage renal 16 disease, and no approved treatment is available in the US to slow disease progression. 17 The mTOR signaling pathway is aberrantly activated in renal cysts, and, while mTOR 18 inhibitors are highly effective in rodent models, clinical trials in ADPKD have been 19 disappointing due to dose-limiting extra-r...

متن کامل

Clinical proof-of-concept trial to assess the therapeutic effect of sirolimus in patients with autosomal dominant polycystic kidney disease: SUISSE ADPKD study

BACKGROUND Currently there is no effective treatment available to retard cyst growth and to prevent the progression to end-stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD). Evidence has recently been obtained from animal experiments that activation of the mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cyst growth and renal...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

دوره 30 1  شماره 

صفحات  -

تاریخ انتشار 2015