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Abstracts
CONTROL OF CYST GROWTH IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): DRUGABLE CHANNEL PATHWAYS
Blazer-Yost, B.L.1' 2, Flaig, S.M.1, Carr, A.2, and Gattone, V.1' 2
1 Department of Biology, Indiana University - Purdue University Indianapolis, Indiana, USA
2 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
ADPKD, a common renal genetic disease, occurs with an incidence of 1 : 400-1000. Cyst expansion progresses slowly, and renal function is typically not compromised until the fifth decade but then the decline to renal failure is precipitous. We are exploring regulatory pathways for drug intervention in both early and late stage disease. Based on our observations that PPARy agonists inhibit CFTR synthesis and that PPARy agonist treatment ameliorates cyst progression in the slowly progressing PCK rat model, we hypothesized that PPARy agonists could be used to treat ADPKD. CFTR is one of the epithelial channels responsible for electrolyte-driven fluid secretion into the cyst lumen causing cyst expansion. PPARy agonists are insulin sensitizing agents used to treat diabetes, albeit with some dose related side effects. Our current data indicate that in the PCK rat after 14 weeks of treatment, both super-pharmacological and sub-pharmacological doses of PPARy agonists significantly decrease renal cyst burden.
In a rapidly progressing model of renal cystic disease, WPK/WPK rats, a 13 day treatment with a PPARy agonist was only effective when used at a sub-pharmacological dose. These data suggest that very low doses of PPARy agonists may be effective life-long therapy for PKD patients, particularly if started at time of diagnosis. Studies were also performed to determine factors involved in renal decline during late stage ADPKD when cyst leakage and rupture is likely. Basolateral exposure to cyst fluid stimulates a Cl- secretory response. The active component in cyst fluid is lysophosphatidic acid. Inhibitor studies in a mouse principal cell line indicate that cyst fluid-stimulated Cl- secretory responses are due to activation of CFTR as well as a Ca2+-activated Cl- channel (CaCC). Interestingly, this stimulated Cl- secretory response is independent of cAMP and is inhibited by BAPTA-AM suggesting a key role for Ca2+ as well as a functional interaction between CFTR and CaCC.
THE WARBURG EFFECT AND METABOLIC CONSEQUENCES IN THE DEVELOPMENT OF APOPTOTIC RESISTANCE IN OSMOTICALLY STRESSED LYMPHOID CELLS
Bortner, C.D., Scoltock, A.B., and Cidlowski, J.A.
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
A high rate of glycolysis, in the presence of oxygen, that results in lactic acid fermentation in the cytosol is a common feature in many cancer cells. This observation, known as the Warburg effect, reflects changes in cellular metabolism and has been used clinically to diagnose and monitor cancer patients. We have developed an immature murine T-cell line through multiple generations of osmotic stress and recovery that have gained this feature of aerobic glycolysis. Interestingly, these osmotic stress cells (S49 (OS)) are also resistant to intrinsic apoptotic stimul, including acute osmotic stress, while remaining sensitive to extrinsic agents. Additionally, these S49 (OS) cells have
gained an inherent regulatory volume increase (RVI) response, and are exquisitely dependent on glucose as an energy source. Our current studies explore the nature of the Warburg effect in regards to cell death and glucose dependence. Specifically we investigate changes at the level of the mitochondria, and the role that various ions have on the Warburg effect and their overall impact on apoptotic resistance. Furthermore, we will present genetic studies that may influence the signal transduction properties related to the Warburg effect and how this may integrate with the development of apoptotic resistance.
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Бюллетень сибирской медицины, 2013, том 12, № 4, с. 24-68
