We have demonstrated that the in a rat model. The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby the IGF-l/Akt/mTOR/p70S6 kinase signaling pathway can lead to apoptosis and proliferation, cyst formation and renal failure in PKD. Novel preliminary data demonstrates activation of Akt and rapamycin-induced inhibition of p70S6K activity in PKD kidneys. Complementary studies will be performed in Han:SPRD rats, PKD2WS25/- and cpk mouse models of PKD and mice with a functional floxed allele of Pkd1.
Specific Aim 1 focuses on in vivo studies using mTOR inhibitors. The effect of mTOR inhibition on apoptosis and proliferation, cyst formation and renal function will test the potential for clinical application.
In Specific Aim 2, we shall investigate the IGF-l/Akt/mTOR/p70S6 kinase signaling pathway in PKD. Our preliminary data demonstrate that rapamycin decreases caspase-3 activation and apoptosis in PKD. Preliminary data also demonstrate that HIF-1a is increased in PKD kidneys. mTOR functions as a positive regulator of HIF-1- dependent responses and rapamycin is known to inhibit HIF-1a. We propose that HIF-1 is proapoptotic in polycystic kidneys and that rapamycin inhibits HIF-1 induced caspase-3 activation and apoptosis.
In Specific Aim#3, we shall determine the time course of HIF-1a activation and the effect of rapamycin on HIF-1a, caspase-3 and apoptosis. The relevance of these studies to clinical ADPKD is substantial and the results should provide leads to altering the course of ADPKD. This is particularly true because of the current availability of mTOR antagonists e.g. rapamycin and its analogs and their proven in vivo beneficial effect as immunosuppressive drugs and cancer treatments.
|Ravichandran, Kameswaran; Ozkok, Abdullah; Wang, Qian et al. (2015) Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in Pkd2. Am J Physiol Renal Physiol 308:F349-57|
|Ravichandran, Kameswaran; Zafar, Iram; Ozkok, Abdullah et al. (2015) An mTOR kinase inhibitor slows disease progression in a rat model of polycystic kidney disease. Nephrol Dial Transplant 30:45-53|
|Ravichandran, Kameswaran; Zafar, Iram; He, Zhibin et al. (2014) An mTOR anti-sense oligonucleotide decreases polycystic kidney disease in mice with a targeted mutation in Pkd2. Hum Mol Genet 23:4919-31|
|Huber, Tobias B; Edelstein, Charles L; Hartleben, Bjorn et al. (2012) Emerging role of autophagy in kidney function, diseases and aging. Autophagy 8:1009-31|
|Belibi, Franck; Zafar, Iram; Ravichandran, Kameswaran et al. (2011) Hypoxia-inducible factor-1Î± (HIF-1Î±) and autophagy in polycystic kidney disease (PKD). Am J Physiol Renal Physiol 300:F1235-43|
|Jani, Alkesh; Zimmerman, Michael; Martin, Jessica et al. (2011) Perfusion storage reduces apoptosis in a porcine kidney model of donation after cardiac death. Transplantation 91:169-75|
|Turkmen, Kultigin; Martin, Jessica; Akcay, Ali et al. (2011) Apoptosis and autophagy in cold preservation ischemia. Transplantation 91:1192-7|
|Belibi, Franck; Ravichandran, Kameswaran; Zafar, Iram et al. (2011) mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease. Am J Physiol Renal Physiol 300:F236-44|
|Jani, Alkesh; Epperson, Elaine; Martin, Jessica et al. (2011) Renal protection from prolonged cold ischemia and warm reperfusion in hibernating squirrels. Transplantation 92:1215-21|
|Lee, D W; Faubel, S; Edelstein, C L (2011) Cytokines in acute kidney injury (AKI). Clin Nephrol 76:165-73|
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