application) This application is to provide support for Jose R. Romero, Ph. D. to allow him protected time for further supervised patient‑oriented research and training to become an independent biomedical scientist. To this end, a formal career development plan and curriculum for his development have been designed. The scientific focus of this application is to study sodium and calcium transport abnormalities at the cellular level that are present in blood cells from insulin resistant hypertensive patients. Various groups have independently shown that insulin resistance and the compensatory hyperinsulinemia are associated with essential hypertension. Erythrocytes, lymphocytes and platelets have been widely used as surrogate cells to what happens in cells that are more closely involved in the hypertensive process. Elevated Na/H exchanger (NHE), hyperinsulinemia and altered cytosolic calcium (Cacyt) handling are frequent abnormalities associated with essential hypertension. Genetic and epidemiological studies have characterized elevated NHE activity in blood cells as an intermediate phenotype in the hypertensive process. Our preliminary findings suggest that NHE activity in red blood cells (RBC) from these patients is insulin resistant but can still modulate sodium transport at high insulin levels. However this response is blunted in comparison to the effect on normotensives. In addition, we have seen that insulin levels correlate with sodium/lithium countertransport, a mode of operation of the NHE. Furthermore, our preliminary data show that incubation of lymphocytes with insulin causes Cacyt to increase in hypertensive patients. These findings have led us to the hypothesis to be tested in this project: insulin resistance is associated with functional defects in sodium and/or calcium transport pathways in hypertensive patients and these pathways are similarly abnormal in target tissues (endothelial cells) of the hypertensive process. To address this problem we have identified the following specific objectives. We will study the effects of insulin and Cacyt on the kinetics of NHE activation in RBC and lymphocytes from hypertensive individuals that have been characterized by markers of insulin resistance. We propose that the phosphorylation state and/or the turnover rate of NHE are enhanced by either Cacyt and/or insulin. We will also study the effect of insulin on Cacyt in lymphocytes from hypertensives with varying degrees of insulin sensitivity. Finally, we will investigate whether the cation alterations observed in blood cells can be seen in primary cultures of vascular endothelial cells obtained from subjects that have been characterized by markers of insulin resistance. Through these mechanisms the insulin resistance and hyperinsulinemia in hypertensive individuals may be linked to NHE abnormalities and/or elevated Cacyt levels. The information obtained from this project will demonstrate the role of insulin resistance in sodium and calcium transport.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK002817-02
Application #
6380174
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
2000-09-30
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$92,880
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Rivera, Alicia; Ferreira, Ana; Bertoni, Danielle et al. (2005) Abnormal regulation of Mg2+ transport via Na/Mg exchanger in sickle erythrocytes. Blood 105:382-6
Romero, Jose R; Rivera, Alicia; Lanca, Vasco et al. (2005) Na+/Ca2+ exchanger activity modulates connective tissue growth factor mRNA expression in transforming growth factor beta1- and Des-Arg10-kallidin-stimulated myofibroblasts. J Biol Chem 280:14378-84
Ferreira, Ana; Rivera, Alicia; Romero, Jose R (2004) Na+/Mg2+ exchange is functionally coupled to the insulin receptor. J Cell Physiol 199:434-40
Romero, Jose R; Suzuka, Sandra M; Nagel, Ronald L et al. (2004) Expression of HbC and HbS, but not HbA, results in activation of K-Cl cotransport activity in transgenic mouse red cells. Blood 103:2384-90
Romero, Jose R; Rivera, Alicia; Conlin, Paul R (2002) Red blood cell Na+/H+ exchange activity is insulin resistant in hypertensive patients. Clin Exp Hypertens 24:277-87
Romero, Jose R; Suzuka, Sandra M; Nagel, Ronald L et al. (2002) Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity. Blood 99:1103-8
Romero, J R; Rivera, A; Monari, A et al. (2002) Increased red cell sodium-lithium countertransport and lymphocyte cytosolic calcium are separate phenotypes in patients with essential hypertension. J Hum Hypertens 16:353-8