Advisor(s)
Jennifer Pollock
Committee Member(s)
Craig Maynard
David Pollock
Laurie Harrington
Meena Madhur
Shannon Bailey
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Joint Health Sciences
Date of Award
9-11-2025
Abstract
Obesity is a major risk factor for cardiovascular and chronic kidney disease. Both inflammation and endothelial dysfunction are hallmark signs of adverse health outcomes in obesity. Previous data from our lab has shown that a 2-week time restricted feeding (TRF) intervention reduces kidney CD3+ (T) cells and fibrosis and improves endothelial function in a mouse model of diet induced obesity (DIO). There is little known about kidney damage and T cells in obesity. We hypothesized that TRF reduces kidney damage in obese mice through mitigating T cell inflammation. We use a 20-week DIO model, with 18 weeks of ad libitum DIO (45% high fat diet) or normal diet (ND, 10% fat) followed by 2 weeks of continued ad libitum feeding or TRF. We found increased kidney CD8+ T cells in DIO mice compared to ND mice in the dark phase, but not the light phase, which was reduced with TRF. DIO mice had increased kidney CD8+ T cell infiltration from the small intestine that was reduced with TRF. Anti-CD8 intervention in DIO showed reduced kidney fibrosis and damage compared to anti-IgG treated DIO mice. Single cell RNA sequencing data revealed that DIO increased, while TRF reduced, the frequency of a specific cluster of CD8+ T cells with the highest number of differentially expressed genes. We were also interested in how endothelial dysfunction may contribute to adverse cardiovascular and kidney outcomes. Histone deacetylases (HDACs), specifically HDAC1, are also known to increase disease risk in obesity. Our lab has shown that overexpression of HDAC1 in endothelial cells inhibits nitric oxide production, suggesting endothelial dysfunction. Thus, we hypothesized that loss of endothelial cell specific HDAC1 improves cardiovascular disease risk in DIO. Our lab generated a tamoxifen inducible endothelial cell specific HDAC1 (iEC-HDAC1) knockout mouse to investigate this question. Our studies reveal that iEC-HDAC1 knockout for the final 2 weeks of DIO reduces aortic stiffness and kidney interstitial fibrosis, while having no effect on diastolic and systolic function in the heart. Taken together, CD8+ T cells and EC-HDAC1 are both critical for kidney and cardiovascular disease risk in DIO.
ProQuest ID
Recommended Citation
Edell, Claudia, "Immune And Endothelial Cell Mechanisms Of Cardiovascular And Kidney Disease Risk In Obesity" (2025). All ETDs from UAB. 7341.
https://digitalcommons.library.uab.edu/etd-collection/7341
