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The Role of Hepatocyte Nuclear Factor 4a in Renal Proximal Tubule Development

Marable, Sierra S
http://orcid.org/0000-0002-2938-0866
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595849621045508

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Nephron segmentation is a poorly understood process that forms four distinct regions of the nephron: the renal corpuscle, the proximal tubule, the loop of Henle, and the distal tubule. Each segment has a specialized function necessary for proper renal filtration. The proximal tubule is the main site of active reabsorption in the nephron, responsible for approximately 65% of total reabsorption. Proximal tubule dysfunction has been implicated in many nephrology disorders, such as renotubular acidosis and Fanconi renotubular syndrome (FRTS), which can lead to chronic kidney disease in adulthood. In order to provide better treatments, it is necessary to understand the molecular mechanisms underlying proximal tubule development. The goal of this dissertation is to determine the molecular mechanisms regulating proximal tubule development. Hepatocyte nuclear factor 4 alpha (Hnf4a) is a transcription factor that is only expressed in the proximal tubules of the kidney. A heterozygous mutation in the HNF4A gene has been identified in patients with FRTS. FRTS is defined as generalized proximal tubular dysfunction characterized by polyuria, polydipsia, glucosuria, proteinuria, and phosphaturia. This suggests that Hnf4a is a key regulator of proximal tubule development and function. However, the role of Hnf4a in proximal tubule development is unknown and there was no mouse model for kidney-specific Hnf4a deletion. Therefore, to investigate the role of Hnf4a in the kidney, we generated two mouse models of nephron-specific Hnf4a deletion. The first mouse model studied featured mosaic deletion of Hnf4a in Six2-expressing nephron progenitors. In this model, Hnf4a mutant mice showed a paucity of proximal tubules in the developing kidney. This paucity led to mutant mice developing FRTS-like symptoms. Hnf4a mutant cells were unable to mature into LTL-high proximal tubules cells, indicating that Hnf4a is required for proximal tubule maturation. In the second mouse model, we investigated the results of complete deletion of Hnf4a in the Osr2-expressing proximal portion of the nephron. In this model, there was complete loss of LTL-high mature proximal tubules causing early postnatal lethality in the mutant mice. These mutant mice showed arrested proximal tubule development with an increase in Cdh6+ progenitors. Transcriptomic and genomic analyses identified transporters genes and metabolism genes are the primary targets of Hnf4a in the kidney. Overall, these results showed that Cdh6+ cells in the developing kidney are proximal tubule progenitors and that Hnf4a is required for the transition of the Cdh6+ progenitors to LTL-high mature proximal tubules. Hnf4a regulates this differentiation via expression of transporter and fatty acid metabolism genes.
Joo-Seop Park, Ph.D. (Committee Chair)
Elif Erkan, M.D. (Committee Member)
S. Steven Potter, Ph.D. (Committee Member)
Katherine Yutzey, Ph.D. (Committee Member)
Aaron Zorn, Ph.D. (Committee Member)
101 p.
Developmental Biology
proximal tubule; kidney development; Hnf4a

Recommended Citations

Citations

  • Marable, S. S. (2020). The Role of Hepatocyte Nuclear Factor 4a in Renal Proximal Tubule Development [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595849621045508

    APA Style (7th edition)

  • Marable, Sierra. The Role of Hepatocyte Nuclear Factor 4a in Renal Proximal Tubule Development. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595849621045508.

    MLA Style (8th edition)

  • Marable, Sierra. "The Role of Hepatocyte Nuclear Factor 4a in Renal Proximal Tubule Development." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595849621045508

    Chicago Manual of Style (17th edition)

ucin1595849621045508
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This open access ETD is published by University of Cincinnati and OhioLINK.