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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL068686-11A1
Application #
8458220
Study Section
Special Emphasis Panel (ZHL1-PPG-S (O1))
Project Start
Project End
Budget Start
2013-02-15
Budget End
2014-01-31
Support Year
11
Fiscal Year
2013
Total Cost
$203,348
Indirect Cost
$73,576
Name
Georgetown University
Department
Type
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Diao, Zhenyu; Asico, Laureano D; Villar, Van Anthony M et al. (2017) Increased renal oxidative stress in salt-sensitive human GRK4?486V transgenic mice. Free Radic Biol Med 106:80-90
Pei, Lei; Solis, Glenn; Nguyen, Mien T X et al. (2016) Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126:2509-18
Tojo, Akihiro; Kinugasa, Satoshi; Fujita, Toshiro et al. (2016) A local renal renin-angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats. Diabetes Metab Syndr Obes 9:1-10
Konkalmatt, Prasad R; Asico, Laureano D; Zhang, Yanrong et al. (2016) Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure. JCI Insight 1:
Jose, Pedro A (2016) Gastrorenal communication: sniffing and tasting. Exp Physiol 101:457-8
Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M et al. (2016) Human GRK4?142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension 67:325-34
Zhang, Gensheng; Wang, Qiaoling; Zhou, Qin et al. (2016) Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway. Kidney Blood Press Res 41:129-38
Wang, Renjun; Huang, Qian; Zhou, Rui et al. (2016) Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus. Circ Heart Fail 9:e002261
Jose, Pedro A; Welch, William (2016) Do You Want to Ditch Sodium? Meet Nitric Oxide Synthase 1? at the Macula Densa. J Am Soc Nephrol 27:2217-8
Jose, Pedro A; Yang, Zhiwei; Zeng, Chunyu et al. (2016) The importance of the gastrorenal axis in the control of body sodium homeostasis. Exp Physiol 101:465-70

Showing the most recent 10 out of 194 publications