The long-term goals of this project are to establish the importance and underlying mechanisms mediating the effects of intrarenal ACE-derived Ang II generation on the development of hypertension and renal injury while facilitating the applicant?s transition to an independent career in the field of kidney disease. The kidneys posses all the components of the renin-angiotensin system and therefore are capable of synthesizing Ang II. Because the kidneys play a preponderant role in fluid homeostasis and blood pressure regulation, it is likely that an augmented intrarenal Ang II generation is of cardinal importance for the development of hypertension and renal damage but this has not been determined. Previous studies by the applicant demonstrate that the kidneys from Ang II-infused mice display an augmented angiotensinogen expression and persistence of renin and angiotensin-converting enzyme (ACE) activities that suggest the presence of sustained intrarenal Ang II generation. Recent reports have provided evidence for functional interactions between Ang II and microRNAs. Because a single microRNA can regulate the expression of multiple genes, it is possible that in generating complex phenotypes like hypertension and kidney damage intrarenal Ang II modulates one or several microRNAs. In particular, microRNA 21 (miR-21) has gained recognition in cardiovascular disease because of its involvement in cardiac hypertrophy, apoptosis, inflammation, and as mediator of some Ang II actions, but its role in kidney disease has not been determined. Therefore, the HYPOTHESIS to be tested is that during Ang II-induced hypertension, intrarenal ACE-derived Ang II formation is required in order to augment Ang II levels in the kidney that in turn increase sodium and water retention, increase miR-21 expression, and lead to the progressive development of high blood pressure and renal injury. Experiments will be conducted in the department of Physiology of Tulane University in collaboration with Cedars-Sinai Center from Los Angeles, CA. Tissue-specific ACE knockout mice will be used in order to address this hypothesis and the following SPECIFIC AIMS are proposed: 1) To demonstrate that mice with impaired intrarenal Ang II formation, as a consequence of the absence of ACE in the kidneys, develop lesser increases in intrarenal Ang II content, sodium retention, blood pressure levels and kidney injury during chronic Ang II infusions when compared to wild-type controls. 2) To demonstrate that mice with ACE expression only in the kidneys develop increases in intrarenal Ang II content and sodium retention along with increased blood pressure levels and kidney injury during chronic infusions of the ACE substrate Ang I. 3) To demonstrate that miR-21 is upregulated in the mouse kidney as a consequence of an augmented intrarenal Ang II generation during Ang II-induced hypertension and that this is an important mechanism for the development of hypertension and renal injury.

Public Health Relevance

Angiotensin II is a hormone that plays a major role in renal function, the development of hypertension and kidney damage. An improved understanding of the mechanisms of its formation within the kidneys will provide a rational approach for the development of better diagnostic and therapeutic strategies for hypertension and a variety of renal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
5R00DK083455-04
Application #
8299620
Study Section
Special Emphasis Panel (NSS)
Program Officer
Ketchum, Christian J
Project Start
2011-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$242,916
Indirect Cost
$17,994
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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