Core B will manage the supply of animals to all projects in the program, by initiating and maintaining breeding colonies for multiple strains of genetically engineered mice. In addition, the Core will evaluate cardiovascular and renal function for cohorts of all mice proposed in the program. Consious blood pressure will be measured by radiotelemetryJn mice with reduced renal mass (RRM) to mimic chronic kidney disease and in separate hypertensive mice infused with angiotensin II (Ang II). Renal function and more specifically, components of renal autoregulation will me measured in anesthetized mice. Renal autoregulaiton will be assessed by two methods that will assess both the myogenic response (MR) and tubuloglomerular feedback (TGF) response that constitutes renal autoregulation. The roles of several genes in blood pressure control and the regulation of renal function in these models will be tested in mice with selected gene deletions, gene overexpression or tissue specific deletions. Also, the roles of genes specifically in the kidney will be tested in mice with gene knockdown in the kidney by the delivery of small interfering RNA (siRNA) constructs.
Aim 1 will breed and manage colonies to produce knockout mice for EC-SOD, IC-SOD, p47phox,CD38 eNOS, dopamine-2 receptor (D2-R), paraoxonase-2 (PON-2), and fibroblast growth factor-binding protein-1 (FGF-BP1) for use in 3 projects. In addition, two tissue-specific transgenic strains, p22phox and catalase in vascular smooth muscle cells (VSMCp22phox tg;VSMCcat tg) will be bred from stock .
Aim 2 will develop mouse models of CKD and hypertension in each of the mouse strains. CKD will be mimicked by surgical reduction of 5/6ths of the kidney at 8-10 weeks of age. Hypertension will be achieved by placement of osmotic minipumps that infuse Ang II at a low pressor dose for 4 weeks.
Aim 3 will measure conscious blood pressure, renal function and renal autoregulation in cohorts of each group of mice. Conscious MAP, heart rate and renal blood flow and GFR, RBF, 0 0 2 under anesthesia will be measured in these mice for the following projects.
The ability of the kidney to adjust to long-term disease and to hypertension predicts the survival of these patients. How the kidney makes those adjustments will help these investigators identify pathways that can be targeted in the treatment of kidney disease and injury. Understanding renal autoregulation is an important component to how the kidney adjusts and protects the patient.
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|Yang, Yu; Cuevas, Santiago; Yang, Sufei et al. (2014) Sestrin2 decreases renal oxidative stress, lowers blood pressure, and mediates dopamine D2 receptor-induced inhibition of reactive oxygen species production. Hypertension 64:825-32|
|Tao, Rong-Rong; Wang, Huan; Hong, Ling-Juan et al. (2014) Nitrosative stress induces peroxiredoxin 1 ubiquitination during ischemic insult via E6AP activation in endothelial cells both in vitro and in vivo. Antioxid Redox Signal 21:1-16|
|Jiang, Xiaoliang; Konkalmatt, Prasad; Yang, Yu et al. (2014) Single-nucleotide polymorphisms of the dopamine D2 receptor increase inflammation and fibrosis in human renal proximal tubule cells. Hypertension 63:e74-80|
|Araujo, Magali; Wilcox, Christopher S (2014) Oxidative stress in hypertension: role of the kidney. Antioxid Redox Signal 20:74-101|
|Yu, Peiying; Han, Weixing; Villar, Van Anthony M et al. (2014) Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells. Redox Biol 2:570-9|
|Huang, Ji-Yun; Li, Li-Tao; Wang, Huan et al. (2014) In vivo two-photon fluorescence microscopy reveals disturbed cerebral capillary blood flow and increased susceptibility to ischemic insults in diabetic mice. CNS Neurosci Ther 20:816-22|
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