Intrarenal Angiotensin II generation during Angiotensin II-induced hypertension

Summary

Principal Investigator: ROMER ANDRES GONZALEZ-VILLALOBOS
Abstract: 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[unreadable]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.
Funding Period: 2011-08-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme
    Kenneth E Bernstein
    Cedars Sinai Medical Center, 8700 Beverly Boulevard, Davis 2021, Los Angeles, CA 90048, USA
    Pharmacol Rev 65:1-46. 2013
  2. pmc The absence of intrarenal ACE protects against hypertension
    Romer A Gonzalez-Villalobos
    Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    J Clin Invest 123:2011-23. 2013
  3. pmc Rediscovering ACE: novel insights into the many roles of the angiotensin-converting enzyme
    Romer A Gonzalez-Villalobos
    Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
    J Mol Med (Berl) 91:1143-54. 2013
  4. pmc Renal angiotensin-converting enzyme and blood pressure control
    Kenneth E Bernstein
    Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
    Curr Opin Nephrol Hypertens 23:106-12. 2014
  5. pmc ACE overexpression in myelomonocytic cells: effect on a mouse model of Alzheimer's disease
    Maya Koronyo-Hamaoui
    Department of Neurosurgery and the Maxine Dunitz Neurosurgical Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
    Curr Hypertens Rep 16:444. 2014

Research Grants

  1. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
  2. Novel Mechanisms and Therapies in Heart Failure
    Howard A Rockman; Fiscal Year: 2013
  3. Protein-glycan Interactions in the Vascular System
    Lijun Xia; Fiscal Year: 2013
  4. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
  5. Regulation of AT1R-signaling and pathology in vessels through microRNA
    Sadashiva S Karnik; Fiscal Year: 2013
  6. Genetic &Physiological Basis of Salt-sensitive Hypertension
    Allen W Cowley; Fiscal Year: 2013
  7. Role of CD247 in Salt-Sensitive Hypertension and Renal Disease
    David L Mattson; Fiscal Year: 2013
  8. COBRE in Lipidomics and Pathobiology
    Besim Ogretmen; Fiscal Year: 2013
  9. RAS and Injury
    Kenneth E Bernstein; Fiscal Year: 2013
  10. Study of ANP Receptor: Gene Targeting and Expression
    Kailash N Pandey; Fiscal Year: 2013

Detail Information

Publications8

  1. pmc A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme
    Kenneth E Bernstein
    Cedars Sinai Medical Center, 8700 Beverly Boulevard, Davis 2021, Los Angeles, CA 90048, USA
    Pharmacol Rev 65:1-46. 2013
    ..In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors...
  2. pmc The absence of intrarenal ACE protects against hypertension
    Romer A Gonzalez-Villalobos
    Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    J Clin Invest 123:2011-23. 2013
    ..In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension...
  3. pmc Rediscovering ACE: novel insights into the many roles of the angiotensin-converting enzyme
    Romer A Gonzalez-Villalobos
    Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
    J Mol Med (Berl) 91:1143-54. 2013
    ..It is these features which explain why ACE makes important contributions to many different physiological processes including renal development, blood pressure control, inflammation, and immunity. ..
  4. pmc Renal angiotensin-converting enzyme and blood pressure control
    Kenneth E Bernstein
    Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
    Curr Opin Nephrol Hypertens 23:106-12. 2014
    ..This review presents novel findings regarding the renal angiotensin-converting enzyme (ACE) and its role in blood pressure (BP) control...
  5. pmc ACE overexpression in myelomonocytic cells: effect on a mouse model of Alzheimer's disease
    Maya Koronyo-Hamaoui
    Department of Neurosurgery and the Maxine Dunitz Neurosurgical Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
    Curr Hypertens Rep 16:444. 2014
    ....

Research Grants30

  1. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  2. Novel Mechanisms and Therapies in Heart Failure
    Howard A Rockman; Fiscal Year: 2013
    ..The results will be used to define novel strategies for manipulation of these recently discovered mechanisms for the therapy of patients with heart failure. ..
  3. Protein-glycan Interactions in the Vascular System
    Lijun Xia; Fiscal Year: 2013
    ..This information may suggest new approaches to treat heart attacks, strokes, and other cardiovascular disorders. ..
  4. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  5. Regulation of AT1R-signaling and pathology in vessels through microRNA
    Sadashiva S Karnik; Fiscal Year: 2013
    ..There is potential relevance for this knowledge base in understanding normal functioning aorta, vasculature in brain, kidney and heart, as well as the pathology of heart failure, atherosclerosis and aortic aneurysm. ..
  6. Genetic &Physiological Basis of Salt-sensitive Hypertension
    Allen W Cowley; Fiscal Year: 2013
    ..The collaborative research of this PPG will be supported by Administrative Core A, Genomic and Transgenic Core B, and the Research Services Core C. ..
  7. Role of CD247 in Salt-Sensitive Hypertension and Renal Disease
    David L Mattson; Fiscal Year: 2013
    ....
  8. COBRE in Lipidomics and Pathobiology
    Besim Ogretmen; Fiscal Year: 2013
    ....
  9. RAS and Injury
    Kenneth E Bernstein; Fiscal Year: 2013
    ..Given the very large number of people taking ACE inhibitors, and the fact that all ACE inhibitors raise AcSDKP level, it is important to understand the physiologic effects of high AcSDKP. ..
  10. Study of ANP Receptor: Gene Targeting and Expression
    Kailash N Pandey; Fiscal Year: 2013
    ..The resulting knowledge should yield new molecular therapeutic targets for the treatment of hypertension and prevention of hypertension-related cardiovascular disorders. ..
  11. ROLE OF ENHANCERS REGULATING RENIN GENE EXPRESSION
    CURT DANIEL SIGMUND; Fiscal Year: 2013
    ..These studies will link transcriptional signals regulating the renin gene with physiological endpoints controlling blood pressure and metabolism which may go awry in hypertension. I..
  12. Novel EP receptor antagonists for the treatment of hypertension and of diabetes
    Richard M Breyer; Fiscal Year: 2013
    ....
  13. Regulation of Adrenal Vascular Tone by Steroidogenic Cells
    WILLIAM BRYSON CAMPBELL; Fiscal Year: 2013
    ..APA may determine whether ZG cell-mediated EET- and/or endothelial-mediated NO mechanisms oppose the constriction by AII and maintain ABF in high renin states. ..
  14. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  15. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  16. Autocoids in Hypertension: Pathogenesis and End Organ Damage
    Oscar A Carretero; Fiscal Year: 2013
    ..Te PPG provides integration of our efforts, collaboration, sharing of ideas and expertise, thus accelerating acquisition of knowledge on the causes of hypertension and EOD. (End of Abstract) ..
  17. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  18. Multiphoton imaging of the juxtaglomerular apparatus
    Janos Peti-Peterdi; Fiscal Year: 2013
    ..In this proposal we will directly visualize novel mechanisms in the kidney using a state-of- the-art imaging technology which will allow us to discover how the kidney operates in real time to control blood volume and pressure. ..
  19. Renal AT2 Receptors in Hypertension
    ROBERT MUNSON CAREY; Fiscal Year: 2013
    ..This application will increase our understanding of the mechanisms whereby the kidney renin-angiotensin system regulates salt and water excretion, suggesting new molecular targets for the treatment and prevention of hypertension. ..
  20. Role of micro RNAs in renin cell differentiation
    ROBERTO ARIEL GOMEZ; Fiscal Year: 2013
    ..Information gained from the proposed studies may help children and adults affected by kidney diseases and hypertension. ..
  21. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  22. VASODEPRESSOR MECHANISMS IN HYPERTENSION
    Carlos M Ferrario; Fiscal Year: 2013
    ..Understanding the regulation of this system is vital to the prevention of cardiovascular disease as well as in the design of effective therapies to reduce the consequences of the disease. ..
  23. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  24. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..