Metabolism of Endothelial Dysfunction in Renal Disease

Summary

Principal Investigator: Leticia Castillo
Abstract: DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is a major cause of death among End Stage Renal Disease (ESRD) patients. CVD is caused in part by endothelial dysfunction. Three metabolic pathways have a major role in the regulation of endothelial function: the L-arginine-Nitric Oxide (NO) pathway, the methionine-homocysteine cycle and the asymmetric dimethylarginine (ADMA). This application is a comprehensive study, aimed at integrating metabolic, nutritional, physiologic and genetic aspects of endothelial dysfunction in renal patients. We will conduct a randomized, controlled, mechanistic study on the in vivo homeostasis of these metabolic pathways, and their influence on endothelial dysfunction of renal patients, and in healthy controls. The influence of dietary supplementation with arginine and folic acid on these metabolic pathways will also be explored. Relevant enzymatic genotype (MTHFR and DDAH), will be correlated with the metabolic phenotype. We hypothesize that dysregulation of the metabolism of the L-arginine-NO pathway, the methionine-homocysteine cycle and ADMA kinetics contributes to endothelial dysfunction and that arginine and folic acid supplementation will improve homeostais of these pathways. The aims are: (1) to assess NO bioavailability in CRD and ESRD patients and in healthy controls in relation to: (l.a) whole body rates of NO and arginine synthesis, methionine transmethylation, homocysteine re-methylation and transulfuration, cysteine oxidation and the rates of synthesis of whole blood glutathione, by conducting primed, constant intravenous infusions of the stable isotope tracers L4guanidino 15N2] arginine, L-2H3-methyl]methionine and L- I) 3C]methionine;L-' 3Cureido]citrulline and L-' 3C]cysteine. (l.b) The plasma concentrations of the asymmetric dimethyl arginine (ADMA) and activity of DDAH. (l.c) The differences of these metabolic parameters across the three groups. And (2) To explore the regulatory effects of a 4-week dietary supplementation with (a) arginine or (b) folic acid on the homeostasis of these pathways. The primary endpoint is NO bioavailability and the predictor variables are the kinetic parameters. State-of-the-art mass spectrometric techniques and vascular imaging will be used. The long term objective is to gain new and relevant knowledge about the mechanisms of these processes and to eventually improve the outcome of CVD in these patients.
Funding Period: 2002-09-30 - 2009-12-31
more information: NIH RePORT

Top Publications

  1. pmc Bicarbonate kinetics and predicted energy expenditure in critically ill children
    Jama Sy
    Critical Care Section, Department of Pediatrics, Texas Children s Hospital, Baylor College of Medicine, Houston, TX, USA
    Am J Clin Nutr 88:340-7. 2008
  2. pmc Ontogeny of methionine utilization and splanchnic uptake in critically ill children
    Sascha Verbruggen
    Texas Children s Hospital, Children s Nutrition Research Center, USDA ARS at Baylor College Medicine, 1100 Bates St, Houston, TX 77030, USA
    Am J Physiol Endocrinol Metab 297:E1046-55. 2009
  3. ncbi Parenteral amino acid intakes in critically ill children: a matter of convenience
    Sascha Verbruggen
    Critical Care Section, Department of Pediatrics, Texas Children s Hospital, Baylor College of Medicine, Houston, Texas, USA
    JPEN J Parenter Enteral Nutr 34:329-40. 2010
  4. pmc Adaptation to a long term (4 weeks) arginine- and precursor (glutamate, proline and aspartate)-free diet
    John F Tharakan
    Laboratory of Human Nutrition and Clinical Research Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
    Clin Nutr 27:513-22. 2008
  5. ncbi Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation
    Leticia Castillo
    Critical Care Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
    Pediatr Crit Care Med 10:387-92. 2009

Scientific Experts

  • Leticia Castillo
  • Sascha Verbruggen
  • Jama Sy
  • David Zurakowski
  • William E Gordon
  • John F Tharakan
  • Rachel M Roth
  • Ana Arrivillaga
  • Koen Joosten
  • Johaness van Goudoever
  • Jean Hsu
  • Shaji Chacko
  • Douglas Burrin
  • Manhong Wu
  • Debra Griffin
  • Vernon R Young
  • Larry Jefferson
  • William Heird
  • Jorge Coss-Bu
  • Anand Gourishankar
  • Yong M Yu

Detail Information

Publications5

  1. pmc Bicarbonate kinetics and predicted energy expenditure in critically ill children
    Jama Sy
    Critical Care Section, Department of Pediatrics, Texas Children s Hospital, Baylor College of Medicine, Houston, TX, USA
    Am J Clin Nutr 88:340-7. 2008
    ..Energy expenditure can be determined by bicarbonate dilution kinetics if the energy equivalents of carbon dioxide (food quotient) from the diet ingested are known...
  2. pmc Ontogeny of methionine utilization and splanchnic uptake in critically ill children
    Sascha Verbruggen
    Texas Children s Hospital, Children s Nutrition Research Center, USDA ARS at Baylor College Medicine, 1100 Bates St, Houston, TX 77030, USA
    Am J Physiol Endocrinol Metab 297:E1046-55. 2009
    ..All patients were in negative methionine balance, indicating that the current enteral nutritional support is inadequate in these patients...
  3. ncbi Parenteral amino acid intakes in critically ill children: a matter of convenience
    Sascha Verbruggen
    Critical Care Section, Department of Pediatrics, Texas Children s Hospital, Baylor College of Medicine, Houston, Texas, USA
    JPEN J Parenter Enteral Nutr 34:329-40. 2010
    ....
  4. pmc Adaptation to a long term (4 weeks) arginine- and precursor (glutamate, proline and aspartate)-free diet
    John F Tharakan
    Laboratory of Human Nutrition and Clinical Research Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
    Clin Nutr 27:513-22. 2008
    ..To assess the effects of a 4-week arginine- and precursor-free dietary intake on the regulatory mechanisms of arginine homeostasis in healthy subjects...
  5. ncbi Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation
    Leticia Castillo
    Critical Care Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
    Pediatr Crit Care Med 10:387-92. 2009
    ....