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The Role of Hypoxia in Metabolism and Nephron Development

Cargill, Kasey (2019) The Role of Hypoxia in Metabolism and Nephron Development. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Self-renewing cell populations, such as stem and cancer cells, are highly metabolically active and proliferate by up regulating glycolytic metabolism. Nephron progenitors—which give rise to nephrons—are particularly metabolically active and similarly rely on the glycolysis pathway to drive proliferation. Conversely, as nephron progenitors mature they switch to mitochondrial oxidative phosphorylation coinciding with loss of stemness and rapid differentiation. The mechanism driving this metabolic switch and subsequent differentiation is currently unknown. Oxygenation is an important developmental process tightly regulated by several oxygen-dependent molecules. Although the kidney develops in a relatively hypoxic environment, as the renal vasculature matures, oxygen tension increases. The major hypoxia- responsive pathway expressed in the developing kidney allows for the recruitment of the ubiquitin ligase von Hippel Lindau (VHL) to mark the transcription factor hypoxia-inducible factor 1α (HIF-1α) for proteasomal degradation, a process that we hypothesize leads to normal nephron progenitor differentiation. Prolonged hypoxic insult however, interrupts this pathway such that HIF-1α remains stabilized and continues activation of genes involved in cellular processes including angiogenesis, cell cycle regulation, and metabolism. This investigation reveals a previously unknown mechanism controlling the balance between nephron progenitor self-renewal and differentiation. Collectively, this study found that hypoxia and the VHL/HIF pathway play a critical role in this process by mediating the metabolic switch that is required for nephron progenitor differentiation.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Cargill, Kaseykrc90@pitt.edukrc900000-0003-3082-1937
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairTsang,
Thesis AdvisorSims-Lucas,
Committee MemberEric,
Committee MemberJacqueline,
Committee MemberSruti,
Date: 26 September 2019
Date Type: Publication
Defense Date: 12 July 2019
Approval Date: 26 September 2019
Submission Date: 1 August 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 185
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Genetics and Developmental Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Kidney development, Hypoxia, Nephron, VHL, HIF, Metabolism
Date Deposited: 26 Sep 2019 13:49
Last Modified: 26 Sep 2019 13:49


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