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Investigating Mechanisms of Glomerular Endothelial Injury and Barrier Function in Preeclampsia
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Investigating Mechanisms of Glomerular Endothelial Injury and Barrier Function in Preeclampsia. |
| 개인저자 | Degner, Kenna R. |
| 단체저자명 | The University of Wisconsin - Madison. Endocrinology and Reproductive Physiology. |
| 발행사항 | [S.l.]: The University of Wisconsin - Madison., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 269 p. |
| 기본자료 저록 | Dissertations Abstracts International 80-12B. Dissertation Abstract International |
| ISBN | 9781392259511 |
| 학위논문주기 | Thesis (Ph.D.)--The University of Wisconsin - Madison, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
Publisher info.: Dissertation/Thesis. Advisor: Shah, Dinesh M. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Preeclampsia is a pregnancy specific disorder often associated with renal dysfunction and proteinuria (i.e. protein leakage in the urine). Proteinuria indicates that the barrier function of the kidney is impaired, but the mechanisms responsible remain poorly understood. As a result, therapeutic options for addressing proteinuria are limited. Previous work from our lab and others have suggested that vascular endothelial growth factor (VEGF) may be elevated in the glomerulus in preeclampsia, but a role for elevated VEGF signaling in the development of proteinuria has not previously been explored. Within these studies, we have used a transgenic mouse model and primary glomerular endothelial cells (GEnCs) from female mice to explore VEGF-mediated signaling pathways associated with changes in GEnC barrier function. Herein, we demonstrate that VE-cadherin and Cx43 expression are altered in the kidney of a transgenic mouse model in the same period when we have previously shown proteinuria and glomerular injury. This led us to propose that VEGF-mediated disruption of cell-cell junctions in GEnCs may contribute to reduced GEnC barrier function and proteinuria in preeclampsia. We have further shown that VEGF stimulates a biphasic reduction in GEnC barrier function that is associated with loss in VE-cadherin and ZO-1 expression and membrane-specific localization. To determine if we could prevent the long-term VEGF-mediated loss in GEnC resistance, we explored two signaling pathways associated with barrier function and junctional proteins: c-Src and ERK1/2. We observed that c-Src inhibition alone and in combination with VEGF temporarily reduces GEnC barrier function while paradoxically increasing VE-cadherin expression and membrane localization. Although c-Src inhibition prevents long-term VEGF-mediated loss in GEnC resistance, our observations suggest c-Src is crucial for GEnC barrier function, possibly through protein recycling, and therefore would not make a good therapeutic target. In contrast, ERK1/2 inhibition improves GEnC resistance both alone and in the presence of VEGF although this was not clearly associated with changes in VE-cadherin and ZO-1 expression and membrane localization. Our studies suggest that targeted ERK1/2, but not c-Src, inhibition may provide a future target for addressing impaired GEnC barrier function in preeclampsia. |
| 일반주제명 | Endocrinology. Health sciences. Physiology. |
| 언어 | 영어 |
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