Congenital abnormalities of the kidney and urinary tract (CAKUT) are the major cause of renal failure in childhood. In order to develop more effective preventive and therapeutic interventions, it is important to better understand the molecular pathogenesis of CAKUT. Branching morphogenesis in the developing kidney involves growth and branching of the ureteric bud (UB) and its daughter collecting ducts. Even subtle defects in the efficiency and/or accuracy of this process have profound effects on the ultimate development of the kidney. The renin-angiotensin system (RAS) is required for the proper development of the renal medulla and papilla, since mutations in the genes encoding components of the RAS in mice cause renal papillary hypoplasia, hydronephrosis, and urinary concentrating defect. In addition, the UB branches and surrounding mesenchymal stroma express angiotensinogen (ACT) and angiotensin (ANG) IIAT1/AT2 receptors. These findings imply that UB-derived epithelia are targets for ANG II actions during metanephric kidney development. In this proposal, we will test the overall hypothesis that ANG II regulates both early and late steps of renal collecting system development.
In Aim 1, we will utilize AGT-deficient mice expressing green fluorescent protein in the UB to test the hypothesis that endogenous ANG II is required for UB branching morphogenesis during early metanephric development.
Aim 2 will test the hypothesis that ANG II stimulates papillogenesis during late metanephric development.
Aim 3 will test the hypothesis that transgenic expression of AT1 receptor in the UB of AT1-deficient mice rescues UB growth and branching.
Aim 4 will characterize the cross-talk between the RAS and stromal factors important for UB branching morphogenesis and papillary development. The results of the proposed studies should yield new knowledge on the role of ANG II in UB/papillary growth and development. Such information can be utilized for the design of interventional strategies aimed at the prevention and treatment of CAKUT.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071699-05
Application #
8065538
Study Section
Special Emphasis Panel (ZRG1-RUS-B (04))
Program Officer
Hoshizaki, Deborah K
Project Start
2007-05-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$250,450
Indirect Cost
Name
Tulane University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Song, Renfang; Preston, Graeme; Ichihara, Atsuhiro et al. (2013) Deletion of the prorenin receptor from the ureteric bud causes renal hypodysplasia. PLoS One 8:e63835
Song, Renfang; Preston, Graeme; Yosypiv, Ihor V (2013) Ontogeny of the (pro)renin receptor. Pediatr Res 74:5-10
Song, Renfang; Preston, Graeme; Khalili, Ali et al. (2012) Angiotensin II regulates growth of the developing papillas ex vivo. Am J Physiol Renal Physiol 302:F1112-20
Song, Renfang; Preston, Graeme; Yosypiv, Ihor V (2012) Ontogeny of angiotensin-converting enzyme 2. Pediatr Res 71:13-9
Song, Renfang; Preston, Graeme; Yosypiv, Ihor V (2011) Angiotensin II stimulates in vitro branching morphogenesis of the isolated ureteric bud. Mech Dev 128:359-67
Song, Renfang; Spera, Melissa; Garrett, Colleen et al. (2010) Angiotensin II AT2 receptor regulates ureteric bud morphogenesis. Am J Physiol Renal Physiol 298:F807-17
Song, Renfang; Van Buren, Thomas; Yosypiv, Ihor V (2010) Histone deacetylases are critical regulators of the renin-angiotensin system during ureteric bud branching morphogenesis. Pediatr Res 67:573-8
Song, Renfang; Spera, Melissa; Garrett, Colleen et al. (2010) Angiotensin II-induced activation of c-Ret signaling is critical in ureteric bud branching morphogenesis. Mech Dev 127:21-7
Yosypiv, Ihor V (2009) Renin-angiotensin system-growth factor cross-talk: a novel mechanism for ureteric bud morphogenesis. Pediatr Nephrol 24:1113-20
Yosypiv, Ihor V; Boh, Mary K; Spera, Melissa A et al. (2008) Downregulation of Spry-1, an inhibitor of GDNF/Ret, causes angiotensin II-induced ureteric bud branching. Kidney Int 74:1287-93

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