Nobuyuki Takahashi, MD, PhD
Assistant Professor
Joint Appointment in the Department of Pathology and Laboratory Medicine

Education:

MD, Tohoku University 1989
PhD, Tohoku University 1995

Mechanism of hypertension, diabetic complications, and obesity using genetically engineered animals

Our research is focused on hypertension, preeclampsia, diabetic nephropathy, and obesity. These conditions are likely caused by combinations of small changes in the expression of several genes. However, it is difficult to identify the culprit genes in humans because our heterogeneous genetic background obscures the gene effects. To circumvent this problem, we generate and use genetically engineered mouse models combined with computer simulations to help unravel the complex interactions and pathophysiology of these common diseases. This approach is expected to help develop new ways of diagnosing, preventing and treating these conditions which can have different causes in different individuals even though they appear similar.

Hypertension : The kidney controls blood volume and blood pressure (BP) as a result of equilibrium between filtration and reabsorption of salt and water. Filtration, which occurs in the glomeruli, is largely controlled by contracting or relaxing the small incoming afferent arterioles of the glomeruli, and cells in the body of glomeruli (mesangium). The small peptide angiotensin II affects all of these functions and thence BP, as do other substances in the blood. Sympathetic nervous activity can also affect kidney function. The generation of angiotensin II needs renin, an enzyme secreted from juxtaglomerular cells in the afferent arterioles. The macula densa, a specialized form of the thick ascending limb of renal tubule (see figure), senses the NaCl concentration in the adjacent lumen, and controls afferent arteriole contraction and the synthesis and secretion of renin. But the details of how the macula densa changes these parameters are not clear. We are using fluorescent genes in the mouse so that by fluorescence activated cell sorting (FACS), we can sort out macula densa cells. Characterizing the macula densa cells is expected to bring us to a new understanding of BP regulation.

Preeclampsia: This is a critical condition not infrequently associated with pregnancy. It is characterized by hypertension, proteinuria and edema. It is a significant cause of maternal morbidity and mortality. An increase in the placental expression of sFlt-1, (a soluble form of the receptor for vascular endothelial growth factor and placental growth factor), is associated with and is a likely cause of preeclampsia. We are using mouse models to study the mechanism of preeclampsia with the aim of identifying other genes that exacerbate the condition. These studies should help develop new ways of preventing and treating preeclampsia.

Diabetic nephropathy: Diabetes, like hypertension, is a multigenetic disease. Diabetic nephropathy greatly increases the risk of cardiovascular events. Diabetic individuals homozygous for the D eletion polymorphism (DD) of the gene for angiotensin-converting enzyme (ACE) have higher plasma ACE levels, and are more susceptible to diabetic nephropathy than those with other ACE genotypes (ID and II). Diabetic mice overexpressing ACE develop more severe albuminuria than diabetic mice with wild type levels of the enzyme.

Our computer simulations of BP regulation by the renin angiotensin system illustrated in this figure (Endocrinology 2003; 144: 2184-2190, ©2003 The Endocrine Society) have led us to hypothesize that a decrease in bradykinin (BK) plays the key role in the progression of diabetic nephropathy in individuals with the ACE DD genotype and in mice overexpressing ACE. We are testing this hypothesis by using diabetic mice lacking the bradykinin B2 receptor, the major receptor for BK. However, we still do not know much about what changes in which genes exacerbate diabetic nephropathy. This is largely due to the lack of animal models that are satisfactory surrogates of human diabetic nephropathy. One key problem is that it takes 10 or more years of diabetes before humans develop diabetic nephropathy, and we do not know how to make it happen in the brief time that mice live . Overexpressing the receptor for the advanced glycation end products (RAGE) may expedite the progression of diabetic nephropathy. We are therefore are beginning to use this mouse to screen candidate genes that may exacerbate diabetic nephropathy. Again our aim is to develop new ways to diagnose, prevent and treat diabetic nephropathy and other diabetic complications.

Obesity and blood pressure regulating genes : Metabolic syndrome, or syndrome X, is a collection of health risks that increase the chance of developing heart disease, stroke, and diabetes. The risk factors involved include obesity, hypertension, abnormal blood lipids, glucose intolerance etc. To better understand the pathophysiology of metabolic syndrome, we are investigating the interrelationship between obesity and the genes that regulate BP. For example, we have found that high expression of genes in the renin angiotensin system increases the amount of body fat. Genes responsible for both hypertension and obesity are important drug targets that may lead to more efficient treatment of metabolic syndrome. Metabolic syndrome is a major public health problem because m ore than one in five Americans have various degrees of this syndrome.

Recent Publications:

M. Kakoki, Y-S. Tsai, H-S. Kim, S. Hatada, D.J. Civatta, N. Takahashi, L.W. Arnold, N. Maeda and O. Smithies. Systematic variations in the level of expression of genes by modifying their 3' regions. Developmental Cell 2004; 6: 597-606.

N. Takahashi and O. Smithies. Human genetics, Animals models and computer simulations for studying hypertension. Trends in Genetics 2004: 20: 136-145.

N. Takahashi, J.R. Hagaman, H-S. Kim and O. Smithies. Computer Simulations of Blood Pressure Regulation by Renin Angiotensin System. Endocrinology 2003; 144: 2184-2190.

N. Takahashi, HL. Brooks, J.B. Wade, W. Liu, Y. Kondo, S. Ito, M.A. Knepper, and O. Smithies. Post-transcriptional Compensation for Heterozygous Disruption of the Kidney-Specific NaK2Cl Cotransporter Gene. J. Am. Soc. Nephrol. 2002; 13: 604-610.

N. Takahashi, D.R. Chernavvsky, R.A. Gomez, P. Igarashi, H.J. Gitelman and O. Smithies. Uncompensated polyuria in a mouse model of Bartter's syndrome. Proc. Natl. Acad. Sci. USA. 2000; 97: 5434-5439.

N. Matsukawa, W.J. Grzesik, N. Takahashi, K.N. Pandey, S. Pang, M. Yamauchi and O. Smithies. The natriuretic peptide clearance receptor locally modulates the physiological effects of natriuretic peptide system. Proc. Natl. Acad. Sci. USA. 1999; 96: 7403-7408.

N. Takahashi, O. Smithies. Gene Targeting Approaches to Analyzing Hypertension. J. Am. Soc. Nephrol. 1999; 10: 1598-1605.

N. Takahashi, K. Takeuchi, A. Sugawara, Y. Taniyama, T. Kato, C.S. Wilcox, K. Abe, S. Ito. Structure and Transcriptional function of the 5'-Flanking Region of Rat Thromboxane Receptor Gene. Biochem. Biophys. Res. Comm. 1998; 244: 489-493.

T. Abe, K. Takeuchi, N. Takahashi, Y. Taniyama, and K. Abe. Rat kidney thromboxane receptor: Molecular cloning, signal transduction, and intrarenal expression localization. J. Clin. Invest. 1995; 96: 657-664.

N. Takahashi, Y. Kondo, I. Fujiwara, O. Ito, Y. Igarashi, and K. Abe. Cytosolic Ca 2+ dynamics in hamster ascending thin limb of Henle's loop. Am. J. Physiol. 1995; 268: F1148-F1153.

N. Takahashi, Y. Kondo, O. Ito, Y. Igarashi, and K. Abe. Vasopressin stimulates Cl - transport in the ascending thin limb of Henle's loop. J. Clin. Invest. 1995; 95: 1623-1627.

N. Takahashi, Y. Kondo, O. Ito, Y. Igarashi, and K. Abe. Characterization of Na+ transport in hamster ascending thin limb of Henle's loop. Kidney Int. 1995; 47: 789-794.