Browsing by Author "Flaig, Stephanie"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Effects of Lysophosphatidic Acid (LPA) and Antidiuretic Hormone (ADH) on Cl- Secretory Responses in Polycystic Kidney Disease (PKD)
    (Office of the Vice Chancellor for Research, 2013-04-05) Martinez, Gabriel M.; Flaig, Stephanie; Blazer-Yost, Bonnie L.
    Polycystic kidney disease (PKD) is a genetic disease that causes the formation of fluid-filled cysts in the kidney and other organs such as the liver and pancreas. Kidney function is seemingly unaltered despite substantial cyst development over the first four to six decades of life, but then the decline in renal function is precipitous often leading to complete renal failure in 5 years. Antidiuretic hormone (ADH) causes an increase in Cl- secretion into the cyst lumen, and one of the drugs in human clinical trials for treatment of PKD is an ADH receptor antagonist. The hormone works by stimulating cAMP production, which leads to the Cl- secretion. Interestingly, we have found that cyst fluid from human patients also causes a secretory Cl- flux that can lead to the growth of the remaining intact cysts. The active component of the cyst fluid is LPA, a phospholipid that acts as an extracellular signaling molecule. This secretion is important in late stage disease when large cysts are likely to leak or burst contributing to the rapid decline in renal function. Electrophysiological techniques were implemented to compare the ion fluxes stimulated by ADH and LPA. In the mpkCCDc14 (mouse principal cells of the cortical collecting duct clone 4) cell line we found that the Cl- secretory pathways stimulated by the two factors are separate and independent. Further indication of this separation is our finding that LPA stimulation does not increase cAMP levels. Therefore we have identified an additional target for potential pharmaceutical intervention in the treatment of PKD.
  • Thumbnail Image
    Item
    Epinephrine stimulation of anion secretion in the Calu-3 serous cell model
    (American Physiological Society (APS), 2014-05-15) Banga, Amiraj; Flaig, Stephanie; Lewis, Shanta; Winfree, Seth; Blazer-Yost, Bonnie L.; Department of Biology, School of Science
    Calu-3 is a well-differentiated human bronchial cell line with the characteristics of the serous cells of airway submucosal glands. The submucosal glands play a major role in mucociliary clearance because they secrete electrolytes that facilitate airway hydration. Given the significance of both long- and short-term β-adrenergic receptor agonists in the treatment of respiratory diseases, it is important to determine the role of these receptors and their ligands in normal physiological function. The present studies were designed to characterize the effect of epinephrine, the naturally occurring β-adrenergic receptor agonist, on electrolyte transport of the airway serous cells. Interestingly, epinephrine stimulated two anion secretory channels, the cystic fibrosis transmembrane conductance regulator and a Ca2+-activated Cl− channel, with the characteristics of transmembrane protein 16A, thereby potentially altering mucociliary clearance via multiple channels. Consistent with the dual channel activation, epinephrine treatment resulted in increases in both intracellular cAMP and Ca2+. Furthermore, the present results extend previous reports indicating that the two anion channels are functionally linked.
  • Thumbnail Image
    Item
    LOW DOSE PPARγ AGONIST INHIBITION OF CYST GROWTH IN THE PCK RAT MODEL OF POLYCYSTIC KIDNEY DISEASE
    (Office of the Vice Chancellor for Research, 2012-04-13) Flaig, Stephanie; Carr, Alexander; Gattone, Vincent; Blazer-Yost, Bonnie L.
    Polycystic kidney diseases (PKD) are genetic disorders characterized by fluid-filled cysts in kidney tubules and liver bile ducts that enlarge during the patient’s life commonly progressing to renal failure in midlife. Cyst enlarge-ment is due in part, to Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Our previous studies demonstrat-ed that PPARγ agonists, insulin-sensitizing drugs used to treat diabetes, in-hibit Cl- secretion by renal collecting duct principal cells via decreased CFTR synthesis. The dose response curves for Cl- transport paralleled the EC50’s for receptor transactivation with a leftward shift, suggesting an increased sensitivity for inhibition of Cl- secretion. Our previous preclinical studies showed that high (20 mg/kg BW) dose pioglitazone, a PPARγ agonist, inhib-ited cyst growth in the PCK rat model, which is orthologous to a human form of PKD. PCK rats were fed a diet containing 3 doses of rosiglitazone (4, 0.4, and 0.04 mg/kg BW) for 24 weeks starting at weaning. 4.0 mg/kg BW rosig-litazone is analogous to 20 mg/kg BW pioglitazone used in the previous study. At the end of the study, urine, serum, kidney, liver, and heart were collected for analysis. There was a significant decrease in total kidney weight, kidney weight as a percent of body weight, and renal cyst volume in the lowest does (0.04 mg/kg BW). There was no significance difference in the other doses, and the liver and heart were not changed significantly. This showed both pioglitazone and rosiglitazone were effective in inhibiting cyst growth in the PCK rat indicating a class action of PPARγ agonists. Important-ly, the rodent data substantiated the previous tissue culture data showing that a very low dose of rosiglitazone is effective in treatment of PKD.