Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD)
Abstract
ADPKD is the most common life-threatening hereditary disease in the United States. ADPKD results in cysts in the kidney that progressively enlarge and destroy the kidney resulting in kidney failure. ADPKD may be as common as 1 in 400 persons and occurs all over the world in all racial and ethnic groups. ADPKD accounts for about 5%-10% of end-stage renal failure in the United States requiring dialysis and renal transplantation. Six percent of patients on the kidney transplant waitlist in the United States have ADPKD. Unfortunately, there is no effective Food and Drug Administration (FDA)-approved treatment for ADPKD. Human and experimental data provide strong evidence that an abnormal increase in the number of tubular cells lining the cysts (proliferation) plays a crucial role in cyst development and/or growth in PKD. Sirolimus, an FDA-approved immunosuppressive and anti-cancer drug, is a potent anti-proliferative drug that indirectly inhibits mammalian target of rapamycin complex 1 (mTORC1), a pro-proliferative pathway present in most cells in the body. In 2005, we were the first to demonstrate that sirolimus markedly decreases tubular cell proliferation, kidney size, and renal failure in a rat model of PKD. However, two recent studies in the New England Journal of Medicine on sirolimus or its derivative everolimus (rapalogues) in humans with ADPKD were very unimpressive. While there are multiple reasons for the unimpressive effect rapalogues in human PKD, one possible reason is that while sirolimus indirectly inhibits mTORC1, it may not have an effect on other pro-proliferative mTORC1 signaling pathways like 4E-BP1 and the pro-proliferative mTORC2 pathway. The genetic studies (Pkd1 -/- mice with additional knockout of mTORC1 or 2 or both) will offer mechanistic insights into novel mTORC1 and 2 signaling pathways and the failure of rapalogues in PKD. 4E-BP1 is a proliferative signaling molecule downstream of mTORC1 that is not inhibited by rapalogues. AktSer473, PKCalpha, and SGK1 are signaling molecules downstream of mTORC2. The mTOR kinase inhibitors (TORKs) inhibit both mTORC1 and 2 and are in human studies in cancer. The pharmacological studies (4EBP1 inhibition, AktSer473, PKCalpha, or SGK1 inhibition and TORKs) will provide insights into future therapies for PKD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610172
Entities
People
- Charles Edelstein
Organizations
- United States Army
- University of Colorado Denver