Principal Investigator/Program Director (Last, first, middle): FoS?? Agnes B. cardiovascular complications in ch^Jkn with chronic kidney disease, Jabs p^Pbses to test if carotid artery intima media thickness can be used as a surrogate marker for the risk of cardiovascular complications. The Pilot and Feasibility Project component for this competing renewal provides an ideal mechanism to support such studies. Thus, Jabs' project in humans, proposed as a pilot study, and Kon's project in mice are complementary and mutually intellectually stimulating. During the initial phenotype analyses on mutant mice lacking some component of RAS, it was found that angiotensin is involved in the ontogeny of the kidney and urinary tract. The observations necessitated the Center to interact closely with the Pediatric Urology group in Vanderbilt. These collaborations done in the Center laboratories resulted in a number of productive research studies on both the Center side and the Pediatric Urology side. To further expand the scientific depth in their research, the Pediatric Research group recruited Upadhya to consult with the Center. Upadhya, a geneticist by training, had focused her research on the genetics of polycystic kidney disease (PKD). Apart from the genes responsible for the manifestation of cyst formation per se, the loss of renal function in PKD is determined by interstitial changes, notably inflammation and scarring. Through the collaborative arrangement with the Center that has been established since her arrival at Vanderbilt, Upadhya proposes a pilot project to expand her research horizon to the genetic and molecular biological mechanisms of the interstitial changes in PKD. As he planned in the previous proposal, Matsusaka successfully generated homozygous deletion mutants for both Renl and Ren2. After an initial observation and publication from the mutants, detailed phenotype analyses are under way. The initial goal after generating several mutant mouse models, including angiotensinogen knock outs, type 1 receptor knock outs, and renin knock outs, is to study the role and the mechanism of angiotensin in renal diseases. In this regard, many mice strains are resistant to development of glomerular diseases, including subtotal nephrectomy model, that have been widely studied in the rat. In search for mouse models of glomerular disease, Matsusaka identified a unique approach, which is likely to be successful in view of the supportive literature. He has thus far been successful in producing transgenic mouse models and gene targeted mouse models, and is now proposing a pilot project of generating a new mouse model of glomerular epithelial cell injury that is linked to progressive renal failure. SECTION M PUBLICATIONS, MANUSCRIPTS, AND ABSTRACTS THAT HAVE RESULTED FROM THE CENTER GRANT 1997: Chen X, Li W, Yoshida H, Tsuchida S, NishimuraH, Takemoto F, Okubo S, Fogo A, Matsusaka T, Ichikawa I: Targeting deletion of angiotensin type IB receptor gene in the mouse. Am J Physiol 272: F 299-304, 1997. Fogo A, Kon V: Pathophysiology of progressive renal disease. In: Immunologic Renal Diseases. Eds. Neilson EG, Couser WG. Raven Press, New York, NY pp. 683-704, 1997. ! Fogo A: Adaptation in progression of renal injury. In: Comprehensive Toxicology. Volume 7: Kidney in Toxicology. Series Eds. Sipes IG, McQueen CA, Gandolfi AJ. Volume Ed. Goldstein RS. Elsevier Science, Oxford, England, pp. 159-179, 1997. Ichikawa I, Hunley TE, Kon V, Fogo A, Matsusaka T: Gene Targeting: general principles with a specific perspective on the renin-angiotensin system. In: International Yearbook of Nephrology, Eds. L Fine, VE Andreucci, Oxford University Press, NY Ch 3, ppl-34, 1997. Matsusaka T, Fogo A, Ichikawa I: Targeting the Genes of the Renin Angiotensin Receptors. Semin Nephrol 17: 396-403, 1997. Matsusaka T, Ichikawa I: Biological functions of angiotensin and its receptors. Annu Rev Physiol 59:395-412, 1997. PHS 398 (Rev. 4/98) Page 2(? T Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. Principal Investigator/Program Director (Last, first, middle): F?g?. Agnes B. Matsusaka T, Ichikawa I: Gene fueling in nephrology. Exp Nephrol 5:1^^73, 1997. Nishimura H, Matsusaka T, Fogo A, Kon V, Ichikawa I: A novel in vivo mechanism for angiotensin type 1 receptor regulation. Kidney Int 52: 345-355, 1997. Okubo S, Niimura F, Nishimura H, Takemoto F, Fogo A, Matsusaka T, Ichikawa I: Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest 99: 855-860, 1997. Okubo S, Ichikawa I: Role of angiotensin: insight from gene targeting studies. KidneyInt Suppl 63: S7-9, 1997. Yoshida H, Kon V, Ichikawa I: Polymorphisms of the renin-angiotensin system genes in slowly progressive renal diseases. Kidney Int 50: 732-744, 1997. 1998: Brock JW III,Hunley TE, Adams MC, Kon V: Review article: Role of renin-angiotensin system in disorders of urinary tract. J Urol 160:1812, 1998. Fogo AB, Vaughan DE: Compound interest: ACE and PAI-1 polymorphisms and risk of thrombosis and fibrosis. Invited Editorial. Kidney Int 54:1765-1766,1998. Ichikawa I: A bridge over troubled water.. .mixed water and electrolyte disorders. Pediatr Nephrol 12: 160-167, 1998. Li W, Ye Y, Fu B, Wang J, Yu L, Ichiki T, Inagami T, Ichikawa I, Chen X: Genetic deletion of AT2 receptor antagonizes angiotensin H-induced apoptosis in fibroblasts of the mouse embryo. Biochem Biophys Res Commun 250: 72-76, 1998. Ma J, Nishimura H, Fogo A, Kon V, Inagami T, Ichikawa I: Accelerated fibrosis and collagen deposition develop in the renal interstitiumof angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int 53: 937-944, 1998. Miyazaki Y, Tsuchida S, Nishimura H, Pope JC IV,Harris RC, McKanna JM, Inagami T, Hogan BLM, Fogo A, Ichikawa I: Angiotensin induces the urinary peristaltic machinery during the perinatal period. J Clin Invest 102:1489-1497, 1998. Nakagome K, Ichikawa I, Kanno O, Akaho R, Suzuki M, Takazawa S, Watanabe H, Kazamatsuri H. Overnight effects of triazolam on cognitive function: an event-related potentials study. Neuropsychobiology 38: 232- 240, 1998. Okubo S, Niimura F, Matsusaka T, Kon V, Fogo A, Inagami T, Hogan BLM, Ichikawa I: Angiotensin gene null mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption. Kidney Int 53: 617-625, 1998. Pope, JC IV, Nishimura H, Ichikawa I: Role of angiotensin in the development of the kidney and urinary tract; Nephrologie 19: 433-436, 1998. Stoneking BJ, Hunley TE, Nishimura H, Ma J, Fogo A, Inagami T, Tamura M, Adams MC, Brock JW III,Kon V: Renal angiotensin converting enzyme promotes renal damage during ureteral obstruction. J Urol 160:1070-1074, 1998. Tsuchida S, Matsusaka T, Chen X, Okubo S, Niimura F, Nishimura H, Fogo A, Utsunomiya H, Inagami T, Ichikawa I: Murine double nullizygotes of the angiotensin type 1A and type IB receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes.J Clin Invest 101: 755-760, 1998. Yerkes E, Nishimura H, Miyazaki Y, Tsuchida S, Brock JW III,Ichikawa I: Role of angiotensin in the congenital anomalies of the kidneyand urinarytract in the mouse and the human. Kidney Int Suppl 67: 575-77,1998. 1999: Cheng HF, Wang JL, Zhang MZ, Miyazaki Y, Ichikawa I, McKanna JA, Harris RC: Angiotensin II attenuates renal cortical cyclooxygenase-2 expression. J Clin Invest 103: 953-961, 1999. Fogo A, Kon V: Pathophysiology of Progressive Renal Disease. In: Pediatric Nephrology, 4th Ed. Editors: M Barratt, ED Avner, W Harmon. Baltimore: Williamsand Wilkins, 1183-1196, 1999. Fogo AB: Current concepts in glomerulosclerosis. Am J Kidney Dis 34:LIV-VI, 1999. PHS 398 (Rev. 4/98) Page Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. Principal Investigator/Program Director (Last, first, middle): Fogo, Agnes B. Fogo AB: Mesangial matrix mo^ption and glomerulosclerosis. Exp Nepl^pl 7:147-159, 1999. Fogo AB: New Insights into the renin-angiotensin system and hypertensive renal disease. Curr Hypertension Reports 1:187-194,1999. Hohenfellner K, Fogo A, Kon V: Renin-angiotensin genes in renal development and the occurrence and progression of renal diseases. Semin Nephrol 19:148-154,1999. Hohenfellner K, Hunley TE, Brezinska R, Shyr Y, Breener W, Habermebl P, Kon V: ACE I/D gene polymorphism predicts renal damage in congenital uropathies. Pediatr Nephrol 13:514-518,1999. Hohenfellner K, Hunley TE, Schloemer C, Brenner W, Yerkes E, Zepp F, Brock JW III,Kon V.: Angiotensin type 2 receptor is important in the normal development of the ureter. Pediatr Nephrol. 13:187-91,1999. Hohenfellner K, Hunley TE, Yerkes E, Habermehl P, Hohenfellner R, Kon V: Angiotensin II, type 2 receptor in the development of vesico-ureteric reflux. BJU 83: 318-22,1999. Johnson RJ, Kivlighn SD, Kim Y-G, Suga S, Fogo AB: Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis 33:225- 234,1999. Matsusaka T, Katori H, Inagami T, Fogo A, Ichikawa I: Communication between myocytes and fibroblasts in cardiac remodeling in angiotensin chimeric mice. J Clin Invest 103:1451-1458, 1999. Matsusaka T, Katori H, Homma T, Ichikawa I: Mechanism of cardiac fibrosis by angiotensin. New insight revealed by genetic engineering. Trends Cardiovasc Med, 9:180-184, 1999. Miyazaki Y, Tsuchida S, Fogo A, Ichikawa I: The renal lesions that develop in neonatal mice during angiotensin inhibition mimic obstructive nephropathy. Kidney Int 55: 1683-1695,1999. Nishimura H, Yerkes E, Hohenfellner K, Miyazaki Y, Ma J, Hunley TE, Yoshida H, Ichiki T, Threadgill D, Phillips JA III, Hogan BLM, Fogo A, Brock JW III, Inagami T, Ichikawa I: Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell 3:1-10, 1999. Nishimura H, Ichikawa I: What have we learned from gene targeting studies for the renin angiotensin system of the kidney? Intern Med, 38:315-323,1999. Pope JC IV,Brock JW III, Adams MC, Stephens FD, Ichikawa I: How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT. J Am Soc Nephrol, 10:2018-2028,1999. Tsuchida S, Miyazaki Y, Matsusaka T, Hunley TE, Inagami T, Fogo A, Ichikawa I: Potent antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature. Kidney Int 56:509-516, 1999. 2000: Brown NJ, Nakamura S, Ma L-J, Nakamura I, Donnert E, Freeman M, Vaughan DE, Fogo AB: Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int 58:1219-1227, 2000. Fogo A: Nephrotic syndrome: molecular and genetic basis. Nephron 85:8-13, 2000. Fogo AB: Glomerular hypertension, abnormal glomerular growth and progression of renal diseases. Kidney Int 57 (suppl 75): S15-S21, 2000. Fogo AB: Pathology of Progressive Nephropathies. Curr Opin Nephrol Hypertension 9:241-246, 2000. Fogo AB: The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosisi (review) Am J Kidney Dis 35:179-188, 2000. Fujinaka H, MiyazakiY, Matsusaka T, Yoshida H, Fogo AB, Inagami T, Ichikawa I: Salutary role for angiotensin in partial urinary tract obstruction. Kidney Int. 58:2018-2027, 2000. Hoyer JR, Fogo AB, Terrell CH, Delaney MM: Immunornorphometric studies of proteinuria in individual deep and superficial nephrons of rats. Lab Invest. 80:1691-1700, 2000. Hunley TE, Tamura M, Stoneking BJ, NishimuraH, Ichiki T, Inagami T, Kon V: The angiotensin type IIreceptor inhibits angiotensin-converting enzyme in AT2 null mutant mice. Kidney Int. 57: 570-577, 2000. Kon V, Ichikawa I: Prospects for gene transfer into renal cells, (review) Kidney Int 57: 2169-2170, 2000. PHS 398 (Rev. 4/98) Page 2.% j"""""""" Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. j Principal Investigator/Program Director (Last, first, middle): F?9?i Agnes B. Ma LJ, Nakamura S, Whitsitt JS^parcantoni C, Davidson JM, Fogo AB:^Pgression of sclerosis in aging by an angiotensin inhibition-induced decrease in PAI-1. Kidney Int 58: 2425-2436, 2000. Matsusaka T, Katori H, Niimura F, Ichikawa I: Angiotensin II as a player in fibrosis. Nephrology, Dialysis, Transplantation 15(Suppl 6): 64-65, 2000. Matsusaka T, Kon V, Takaya J, Katori H, Chen X, Miyazaki J, Homma T, Fogo A, Ichikawa I: Dual renin gene targeting by Cre-mediated interchromosomal recombination. Genomics, 64: 127-31, 2000. Meneton P, Ichikawa I, Inagami T, Schnermann J: Renal physiology of the mouse. Am J Physiol Renal Physiol, 278: F 339-351, 2000. Miyazaki Y, Oshima K, Fogo A, Hogan BL, Ichikawa I: Bone morphogenetic protein 4 regulates the budding
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