Browsing by Author "Gattone, Vincent"

Now showing 1 - 5 of 5
  • 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.
  • Thumbnail Image
    Item
    Pioglitazone Attenuates Cystic Burden in the PCK Rodent Model of Polycystic Kidney Disease
    (2010) Blazer-Yost, Bonnie; Haydon, Julie; Eggleston-Gulyas, Tracy; Chen, Jey-Hsin; Wang, Xiaofang; Gattone, Vincent; Torres, Vicente E.
    Polycystic kidney disease (PKD) is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney tubules and liver bile ducts. Currently, the clinical management of PKD is limited to cyst aspiration, surgical resection or organ transplantation. Based on an observation that PPARγ agonists such as pioglitazone and rosiglitazone decrease mRNA levels of a Cl(-) transport protein, CFTR (cystic fibrosis transmembrane conductance regulator), and the Cl(-) secretory response to vasopressin in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7- or 14-week pioglitazone feeding regimen inhibits renal and hepatic bile duct cyst growth in the PCK rat, a rodent model orthologous to human PKD. These studies provide proof of concept for the mechanism of action of the PPARγ agonists and suggest that this class of drugs may be effective in controlling both renal and hepatic cyst growth and fibrosis in PKD.
  • Thumbnail Image
    Item
    Pioglitazone, an Insulin Sensitizing Drug, Attenuates the Development of Kidney and Liver Disease in the PCK Rodent Model of Polycystic Kidney Disease
    (Office of the Vice Chancellor for Research, 2010-04-09) Blazer-Yost, Bonnie L.; Haydon, Julie; Eggelston, Tracy; Chen, Jey-Hsin; Torres, Vicente E.; Gattone, Vincent
    Polycystic kidney disease is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney and liver. The only treatment currently available is the removal/aspiration of the largest cysts or organ transplantation. Promising pharmaceutical agents in clinical trials interfere with the action of hormones that increase cAMP thereby inhibiting secretion of Cl-, and compensatory fluid flux, into the cysts. Other treatments proposed include chemotherapeutic and immunosuppressive drugs that interfere with cellular proliferation as well as with signaling pathways for Cl- secretion. Long-term use of these agents will have multiple side effects. Based on a recent observation that peroxisome proliferator activated receptor γ agonists such as Actos (pioglitazone) and Avandia (rosiglitazone) decrease mRNA levels of a Cl- transport protein and the Cl- secretory response to vasopressin stimulation in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7 or 14 week feeding regimen of 20 mg/Kg BW pioglitazone inhibits renal and hepatic bile duct cyst growth in a rodent model orthologous to human PKD. In addition, the degree of renal cortical fibrosis was diminished in the pioglitazone-treated animals after 14 weeks. These results suggest that PPARγ agonists may be effective in controlling both renal and hepatic cyst growth and renal fibrotic development in polycystic kidney disease.
  • Thumbnail Image
    Item
    Prospects for mTOR Inhibitor Use in Patients with Polycystic Kidney Disease and Hamartomatous Diseases
    (American Society of Nephrology, 2010-07) Torres, Vicente E.; Boletta, Alessandra; Chapman, Arlene; Gattone, Vincent; Pei, York; Qian, Qi; Wallace, Darren P.; Weimbs, Thomas; Wüthrich, Rudolf P.; Anatomy and Cell Biology, School of Medicine
    Mammalian target of rapamycin (mTOR) is the core component of two complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and analogues. mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human autosomal dominant polycystic kidney disease (ADPKD). mTOR inhibitors impede cell proliferation and cyst growth in polycystic kidney disease (PKD) models. After renal transplantation, two small retrospective studies suggested that mTOR was more effective than calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting vascular remodeling, angiogenesis, and fibrogenesis, mTOR inhibitors may attenuate nephroangiosclerosis, cyst growth, and interstitial fibrosis. Thus, they may benefit ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation, nitric oxide synthesis, and endothelial cell survival (downstream from mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results.
  • Thumbnail Image
    Item
    Recent Activities in the Center for Membrane Biosciences
    (Office of the Vice Chancellor for Research, 2011-04-08) Blazer-Yost, Bonnie L.; Randall, Stephen; Minto, Robert; Birch, Garrison; Haydon, Julie; Bacallao, Robert; Gattone, Vincent; Blacklock, Brenda
    The Center for Membrane Biosciences (CMB) is active in facilitating collaborative research among center members and other IUPUI community members. A number of seed grants have been made and the results from two will be presented. Recent major funding from the NSF supports a CMB-centered program that promotes intensive undergraduate research opportunities. Project 1: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the slow growth of fluid-filled cysts in the kidney tubules and liver bile ducts. We identified LPA (lysophosphatic acid) as a component of cyst fluid that stimulates secretory Cl- and compensatory water flux into cysts through binding of receptors on the basolateral membrane of renal cells. LPA concentrations measured in ADPKD cyst fluid and in normal serum are sufficient to maximally stimulate ion transport. Thus, cyst fluid seepage and/or leakage of vascular LPA into the interstitial space are capable of stimulating secretion from epithelial cells resulting in cyst enlargement. Project 2: Upon the recent acquisition of Center-supported high-resolution mass spectrometers at IUPUI, methods for the analysis of lipid and protein samples to support nascent research endeavors within the CMB are being developed. Identification and quantification of sphingolipids in biological samples as well as other lipidomic experiments will be presented. Project 3: The IUPUI URM Immersion in Interdisciplinary Research in Biological Signaling program targets underrepresented minorities in the biological sciences, and through early and sustained undergraduate research experiences that are intensely mentored at multiple levels, aims to increase the number of underrepresented minorities achieving graduate degrees in the Biological Sciences. The first cohort will begin research in the program during the summer of 2011 and are currently in the selection process.