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

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2015-01, Vol.30 (1), p.45-53
• Main Authors: Ravichandran, Kameswaran, Zafar, Iram, Ozkok, Abdullah, Edelstein, Charles L
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Blood Urea Nitrogen; Caspase 3 - metabolism; Cell Proliferation - drug effects; Disease Progression; Immunoblotting; Indoles - pharmacology; Interleukin-1 - metabolism; Interleukin-6 - metabolism; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes - antagonists & inhibitors; Original; Polycystic Kidney Diseases - drug therapy; Polycystic Kidney Diseases - enzymology; Polycystic Kidney Diseases - pathology; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; Rats; Rats, Sprague-Dawley; TOR Serine-Threonine Kinases - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfu296

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. Male rats were treated with PP242 5 mg/kg/day IP or vehicle for 5 weeks. 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. 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.