Date of Award

8-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

J. Thomas Cunningham

Second Advisor

Steve Wayne Mifflin

Third Advisor

Ann M. Schreihofer

Abstract

Renin-Angiotensin system (RAS) is a peptidergic hormonal system that is known to regulate hemodynamic and fluid balance. Clinical success of RAS inhibitors in several cardiovascular and renal diseases such as hypertension (HTN), chronic heart failure, and diabetic nephropathy underscore its involvement in their pathophysiology. Recent research efforts are not only helping us understand the mechanisms through which RAS orchestrate the pathophysiology of cardiovascular diseases but are also identifying its involvement in other pathological conditions such as mood disorders and cancer. Although, initially identified as an endocrine system in peripheral circulation, the discovery of renin in the brain ushered in the concept of ‘local’ or ‘tissue’ RAS. Now, local RAS components are increasingly identified to be present in nearly all organ systems.

The In the first project we investigated the role played by the communication between circulating Ang II and subfornical organ (SFO), a circumventricular organ lacking blood brain barrier, in chronic intermittent hypoxia (CIH) associated sustained increase in MAP even during period of normoxic breathing. Using viral mediated delivery of shRNA against Ang II type 1a receptors (AT1aR), it was found that the rats that received AT1aRshRNA in their SFO, exhibited increased MAP responses during CIH but their MAP recovered to levels of normoxic control during room air breathing. Also, disruption of this communication led to decreased FosB/ΔFosB staining in the autonomic regions of forebrain. FosB/ΔFosB staining identifies the expression of transcription factor FosB and its splice variant ΔFosB. These transcription factors are known to orchestrate transcriptional adaptations that lead to lasting neuroplastic adaptations. These data suggest that Ang II-SFO communication is essential in neuroplastic adaptations of forebrain autonomic nuclei, which may sustain the CIH associated increase in MAP even during periods of room air breathing.

Second project was initiated to study the mechanisms through which synaptically released Ang II could affect post-synaptic neuronal sensitivity and function. It is known that bile duct ligated rats, an experimental model of cirrhosis, exhibit impaired osmoregulation. We previously reported that bile duct ligated rats show increased presence of a non-specific cation channel (TRPV4) in the hypothalamic membrane extracts. In addition, an activated RAS is also associated with fluid-electrolyte imbalance, a hallmark feature of cirrhosis. In this project it was investigated if Ang II could translocate TRPV4 to neuronal surface in vitro, in a hypothalamic neuronal cell line, 4B. In 4B cells, Ang II incubation was associated with increased TRPV4 localization to the cell membrane and was also associated with increased calcium influx in response to specific TRPV4 agonist, GSK 1016790A. In addition, these effects were completely blocked in the presence of AT1R receptor antagonist (Losartan) and Src kinase inhibitor, PP2. Taken together, these data suggest that Ang II could translocate TRPV4 to neuronal membrane via Src kinase pathway. These observations could explain one of the mechanisms through which Ang II could contribute to the pathophysiological adaptations that lead to increased water retention and dilutional hyponatremia associated with chronic liver failure.

Comments

Saxena, Ashwini, The role of Angiotensin II in central autonomic and endocrine regulation. Doctor of Philosophy (Biomedical Sciences), June 2014. Available online August 2015.

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