Prakasam, Herman Sandeep
(2013)
THE ROLE OF ADENOSINE IN REGULATING URINARY BLADDER FUNCTION AND A1AR-MEDIATED MEMBRANE TRAFFICKING IN UMBRELLA CELLS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The uroepithelium lines the urinary bladder, urethra and the lower renal pelvis. It provides a tight blood-urine barrier that prevents the unregulated movement of solutes, ions and metabolites present in the urine. Apart from forming a robust barrier, a growing body of evidence supports the role of the uroepithelium as a sensory transducer that is sensitive to extracellular biochemical and mechanical stimuli. One of the mediators that is released from the uroepithelium and impacts bladder activity is adenosine. Adenosine is a well-known stress relieving hormone in other organ systems and the bladder lumen is a region of constant stress due to cyclical filling and voiding of urine, therefore I hypothesized that adenosine has an impact on urinary bladder function under stress. First I assessed the mechanism of adenosine turnover and how luminal adenosine affects bladder function. I report that adenosine is released from the mucosal and serosal surfaces of the uroepithelium when the tissue is maximally stretched. The released adenosine it actively turned over by distinct pathways at either surfaces of the uroepithelium. Further, enriching the luminal adenosine concentration by blocking its routes of turnover or by specific activation of apically localized A1AR by using CCPA, bladder function was modulated by decreasing the threshold pressure of bladder voiding. In the second study, I looked at the impact of adenosine on exocytosis and membrane trafficking in umbrella cells. I report that activation of A1AR at the apical surface of umbrella cells increased apical exocytosis in umbrella cells. The apical exocytosis was similar to late phase stress-mediated exocytosis and required transactivation of EGFR. The pathway involved Gi-Gβγ-PLC-PKC and ADAM17 which in-turn cleaved and released HB-EGF leading to EGFR transactivation and downstream ERK1/2 MAPK. Further, Ser811 in the cytoplasmic tail of ADAM17 was important for A1AR-mediated activation of the protein. Finally, ADAM17 was also involved in late-phase stretch-mediated apical exocytosis in rats but not in rabbits. In conclusion, my studies show that adenosine plays a protective role in the bladder both at the organ and cellular level. At the organ level, adenosine alleviates luminal stress by reducing the threshold pressure for voiding and at the cellular level, it triggers apical exocytosis and increase in membrane surface area of umbrella cells thus mitigating the stress induced by mechanical stretching associated with bladder filling.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Prakasam, Herman Sandeep | hep14@pitt.edu | HEP14 | |
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| ETD Committee: |
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| Date: |
28 October 2013 |
| Date Type: |
Publication |
| Defense Date: |
4 October 2013 |
| Approval Date: |
28 October 2013 |
| Submission Date: |
23 October 2013 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
199 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Medicine |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Adenosine, ADAM, EGFR, Bladder, Uroepithelium, Umbrella cells |
| Date Deposited: |
28 Oct 2013 17:46 |
| Last Modified: |
15 Nov 2016 14:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/19932 |
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