Author ORCID Identifier
0000-0003-3643-7266
Date of Award
Fall 12-12-2022
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biology
First Advisor
Dr, Ming-Hui Zou
Second Advisor
Dr. Ping Song
Third Advisor
Dr. John Houghton
Abstract
Chronic Kidney Disease (CKD) has been implicated in multiple conditions including cardiovascular related diseases and Type 2 Diabetes (T2D). Decreased filtration results in accumulation of urea, electrolytes, and uremic which are implicated in disease progression. Examination of the progression of CKD effect on vascular regeneration, and T2D development are necessary. First, examination of CKD progression and buildup of uremic toxin indoxyl sulfate (IS) was undertaken. In vivo and in vitro analysis implicated CKD and IS accumulation in impaired vascular regeneration increasing risk of mortality. CKD and the concomitant increase in IS resulted in impaired regeneration through alteration to vascular smooth muscle (VSMC). VSMCs exhibited alteration in actin cytoskeletal structure, and decreased motility. This was driven by loss of focal adhesion protein focal adhesion kinase (FAK). Loss of FAK resulted in decreased signal transduction for neuronal Wiskott-Aldrich syndrome protein (N-WASP) necessary for activation of actin nucleation complex Arp2/3. Secondly, examination was undertaken into T2D progression. High-fat induced T2D resulted in a significant increase in Neuropilin 1 (Nrp1) expression in vascular endothelial cells. Transmembrane Nrp1 receptor is a single-pass glycoprotein with well-established roles in vascular events, including tumor angiogenesis, hypoxia, and growth factor-mediated signal transduction. Increased expression of Nrp1 led to alteration in insulin signaling. Altered insulin signaling by Nrp1 contributed to insulin resistance. Thus, our studies demonstrate that CKD induced accumulation of IS impaired vascular regeneration through loss of VSMC motility and impaired vascular regeneration. Also, it was determined that T2D induced expression of Nrp1 resulted in altered insulin signaling and exacerbating insulin resistance.
DOI
https://doi.org/10.57709/32600752
Recommended Citation
Carr, Sean, "Inhibition of FAK-Actin pathway by indoxyl sulfate suppresses arteriogenesis in a mouse model of chronic kidney disease." Dissertation, Georgia State University, 2022.
doi: https://doi.org/10.57709/32600752
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