title: Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications.
abstract: The mTOR pathway plays an important role in a number of common renal diseases, including acute kidney injury (AKI), diabetic nephropathy (DN), and polycystic kidney diseases (PKD). The activity of mTOR complex 1 (mTORC1) is necessary for renal regeneration and repair after AKI, and inhibition of mTORC1 by rapamycin has been shown to delay recovery from ischemic AKI in animal studies, and to prolong delayed graft function in humans who have received a kidney transplant. For this reason, administration of rapamycin should be delayed or discontinued in patients with AKI until full recovery of renal function has occurred. On the other hand, inappropriately high mTORC1 activity contributes to the progression of the metabolic syndrome, the development of type 2 diabetes, and the pathogenesis of DN. In addition, chronic hyperactivity of mTORC1, and possibly also mTORC2, contributes to cyst formation and enlargement in a number of forms of PKD. Inhibition of mTOR, using either rapamycin (which inhibits predominantly mTORC1) or "catalytic" inhibitors (which effectively inhibit both mTORC1 and mTORC2), provide exciting possibilities for novel forms of treatment of DN and PKD. In this second part of the review, we will examine the role of mTOR in the pathophysiology of DN and PKD, as well as the potential utility of currently available and newly developed inhibitors of mTOR to slow the progression of DN and/or PKD.
authors.affiliation: Stony Brook Univ. Medical Center, Health Sciences Center, Stony Brook, NY 11794-8166, USA. wilfred.lieberthal@sbumed.org
authors.forename: Wilfred
authors.initials: W
authors.lastname: Lieberthal
authors.forename: Jerrold S
authors.initials: JS
authors.lastname: Levine
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology* / Q000628:therapy; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D007690:Polycystic Kidney Diseases / Q000188:drug therapy / Q000503:physiopathology*; D011506:Proteins / Q000502:physiology; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: C493245:CRTC2 protein, human; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus