161. Associated Cardio-Renal Dysfunction

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161. Associated Cardio-Renal Dysfunction

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Syllabus

Abstract ………………………………………………………………………………………………………………….ii
Acknowledgments……………………………………………………………………………………………………iii
Contributions…………………………………………………………………………………………………………..v
Table of Contents…………………………………………………………………………………………………….vi
Abbreviations………………………………………………………………………………………………………….ix
List of Figures………………………………………………………………………………………………………….xi
List of Tables ………………………………………………………………………………………………………… xiv
List of Appendices …………………………………………………………………………………………………..xv
Chapter 1: Introduction ……………………………………………………………………………………………. 1
1.1 Introduction ……………………………………………………………………………………………………………….2
1.2 Lysine Acetylation and Deacetylation: Reversible Post-Translational Modifications………………..2
1.3 The Discovery of Sir2 ……………………………………………………………………………………………………3
1.4 Members of the Mammalian Sirtuin Family ……………………………………………………………………..3
1.5 Sirt1: The Most Highly Studied Sirtuin……………………………………………………………………………..5
1.5.1 Structure…………………………………………………………………………………………………………………….5
1.5.2 Expression Patterns……………………………………………………………………………………………………..7
1.5.3 Mechanism …………………………………………………………………………………………………………………8
1.5.4 Cytosolic and Nuclear Substrates …………………………………………………………………………………11
1.5.5 Endogenous Regulators of Sirt1 …………………………………………………………………………………..12
1.6 Expression of Sirt1 in Mouse Models …………………………………………………………………………….12
1.7 Sirt1 Activators and Inhibitors ……………………………………………………………………………………..14
1.8 Role of Sirt1 in Disease ……………………………………………………………………………………………….16
1.8.1 Calorie Restriction and its Effect on Aging, Lifespan, and Health span ………………………………16
1.8.2 Kidney Disease…………………………………………………………………………………………………………..19
1.8.3 Cardiovascular Disease ……………………………………………………………………………………………….26
1.8.4 Bridging the Gap Between the Cardiovascular and Renal System Functions………………………29
1.9 Overview………………………………………………………………………………………………………………….31
1.9.1 Rationale…………………………………………………………………………………………………………………..31

1.9.2 Hypotheses……………………………………………………………………………………………………………….31
Chapter 2: Unravelling the role of Sirt1 activity in an aging mouse model…………………………33
2.1 Introduction…………………………………………………………………………………………………………..34
2.2 Specific Aims …………………………………………………………………………………………………………….37
2.3 Methods and Experimental Design ……………………………………………………………………………….38
2.3.1 Generation of the catalytically inactive Sirt1 mouse model……………………………………………..38
2.3.2 Experimental plan for in vivo studies…………………………………………………………………………….39
2.3.3 Statistical analysis………………………………………………………………………………………………………42
2.4 Results……………………………………………………………………………………………………………………..43
2.4.1 Catalytically inactive Sirt1 leads to a reduction in body and kidney weight………………………..43
2.4.2 Male catalytically inactive Sirt1Y/Y mice are less active compared to their wild type and
heterozygous Sirt1+/Y counterparts with similar food intake…………………………………………………….48
2.4.3 Body temperature is consistently lower in the male catalytically inactive Sirt1Y/Y mice ……….49
2.4.4 Catalytically inactive Sirt1Y/Y female mice have decreased survival ………………………………………51
2.5 Discussion ………………………………………………………………………………………………………………..52
Chapter 3: Lack of Sirt1 activity and age-associated kidney function………………………………..56
3.1 Introduction ……………………………………………………………………………………………………………..57
3.2 Specific Aims …………………………………………………………………………………………………………….60
3.3 Materials and Methods ………………………………………………………………………………………………61
3.3.1 Mouse model…………………………………………………………………………………………………………….61
3.3.2 Renal functional parameters ……………………………………………………………………………………….61
3.3.3 Glomerular filtration rate measurement……………………………………………………………………….61
3.3.4 Tissue preparation and histochemistry …………………………………………………………………………62
3.3.5 Estimation of glomerular number ………………………………………………………………………………..63
3.3.6 Measurement of glomerular volume…………………………………………………………………………….66
3.3.7 Assessment of renal structure……………………………………………………………………………………..67
3.3.8 Statistical analysis………………………………………………………………………………………………………67
3.4 Results……………………………………………………………………………………………………………………..68
3.4.1 Catalytically inactive Sirt1 leads to a reduction in total glomerular number ………………………68
3.4.2 Catalytically inactive Sirt1 leads to a reduction in glomerular filtration rate ………………………70
3.4.3 Catalytically inactive Sirt1 does not affect albuminuria …………………………………………………..72
3.4.4 Sirt1 inactivity does not lead to significant changes in glomerular volume ………………………..74

3.4.5 Lack of Sirt1 activity does not lead to an increase in the proportion of glomerular tuft
occupied by mesangial matrix ……………………………………………………………………………………………..74
3.5 Discussion ………………………………………………………………………………………………………………..76
Chapter 4: Lack of Sirt1 and age-associated cardiac dysfunction……………………………………..79
4.1 Introduction ……………………………………………………………………………………………………………..80
4.2 Specific Aims …………………………………………………………………………………………………………….82
4.3 Materials and Methods ………………………………………………………………………………………………83
4.3.1 Mice …………………………………………………………………………………………………………………………83
4.3.2 Cardiac functional parameters …………………………………………………………………………………….83
4.3.3 Tissue preparation and histochemistry …………………………………………………………………………85
4.3.4 Assessment of cardiac structure…………………………………………………………………………………..85
4.3.5 Statistical analysis………………………………………………………………………………………………………85
4.4 Results……………………………………………………………………………………………………………………..86
4.4.1 Catalytically inactive Sirt1 does not affect cardiac function……………………………………………..86
4.4.2 Lack of Sirt1 activity has no effect on systolic cardiac function…………………………………………91
4.4.3 Sirt1 activity does not lead to diastolic dysfunction………………………………………………………..95
4.4.4 Sirt1 activity appears to play a role in contractility and relaxation ……………………………………95
4.4.5 Sirt1 does not play a role in cardiac structure………………………………………………………………100
4.5 Discussion ………………………………………………………………………………………………………………102
Chapter 5: Conclusions & future directions………………………………………………………………..106
5.1 Summary of Results………………………………………………………………………………………………….107
5.2 Limitations ……………………………………………………………………………………………………………..109
5.3 Future directions ……………………………………………………………………………………………………..110
5.4 Conclusions …………………………………………………………………………………………………………….113
References …………………………………………………………………………………………………………..114
Appendices ………………………………………………………………………………………………………….126
Appendix 1: Supplementary Information…………………………………………………………………………..126
Copyright Acknowledgements…………………………………………………………………………………129

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