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A Thesis Entitled Regulatory Mechanisms Of A Thesis entitled Regulatory Mechanisms of Cardiotonic Steroids in Chronic Kidney Disease by Subhanwita Ghosh Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Bioinformatics & Proteomics/Genomics _________________________________________ Dr. David J. Kennedy, Committee Chair _________________________________________ Dr. Sadik Khuder, Committee Member _________________________________________ Dr. Levison Bruce, Committee Member _________________________________________ Dr. Amanda Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo August, 2017 Copyright 2017, Subhanwita Ghosh This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Regulatory Mechanisms of Cardiotonic Steroids in Chronic Kidney Disease by Subhanwita Ghosh Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Bioinformatics & Proteomics/Genomics The University of Toledo August, 2017 Introduction: Cardiotonic steroids (CTSs) are steroid hormones which are elevated in chronic kidney disease (CKD). The 2-pyrone ring structure of CTS is critical for its binding to the Na+/K+-ATPase and subsequent initiation of profibrotic signaling which promotes tissue fibrosis and organ dysfunction underlying cardiac and renal disease. Paraoxonases (PONs) are a family of hydrolytic enzymes which can regulate levels of 2- pyrone structures like those found in CTS, and we have recently discovered that the activity of these enzymes is diminished in setting such as CKD where CTSs are elevated. Hypothesis: We hypothesized that dysregulated expression in the PON gene family is associated with renal disease and that PONs, via their hydrolytic activity, participate in the metabolism and regulation of CTSs. Methods/ Results: We used molecular, biochemical, and bioinformatic approaches to study how PONs regulate CTSs in the setting of renal disease. We first performed a meta- analysis (accessed from NCBI’s Gene Expression Omnibus (GEO) Datasets) of normalized PON isoform gene expression from whole genome microarray data of both peripheral blood mononuclear cells (PBMC’s, n=4 studies, 174 total patients) and renal iii biopsy samples (n=4 studies, 207 total patients), in case-control studies of patients with chronic kidney disease (CKD stage 2-5) and the respective non-CKD controls. From these studies, we noted that PON-1 gene expression was significantly decreased in PBMCs of CKD (Stage 2-3) patients vs non-CKD controls (0.8±0.03 vs 1.0±0.03, p<0.05), however in renal biopsy specimens PON-1 (2.7±0.42 vs 1.0±0.02, p<0.05) and PON-2 (1.5±0.06 vs 1.0±0.04, p<0.01) was significantly increased in CKD (Stage 2-3) patients vs non-CKD controls. We also searched for the genes which are highly correlated such as GADD45B, STK26, IFITM2///IFITM1, ZNF418, etc. with PON genes in the setting of chronic kidney disease. Next, we measured circulating PON-1 protein (ELISA) and activity (as measured with 7-hydroxycoumarin, a specific fluorogenic substrate of PON lactonase/2-pyronase activity) in CKD patients (n=31) and non-CKD controls (n=15). Here we found that PON-1 circulating protein was significantly lower compared to non-CKD controls (p<0.001), and that PON lactonase/2-pyronase activity was also significantly decreased in CKD patients (p<0.0001). Finally, we developed an LC-MS-MS based assay to monitor the potential metabolism of CTSs by PONs. Incubation of the CTS telocinobufagin (TCB) with PON-1 overexpressing HEPG2 cells led to a 2-fold decrease in the intact 2-pyrone form of TCB vs control (p=0.0054). Conclusion: While PON-1 and PON-2 gene expression is increased in renal biopsy samples of CKD patients, PON-1 gene expression is decreased in PBMC’s of CKD patients’ vs controls. Furthermore, circulating levels of PON1 and lactonase activity of PON1are decreased in CKD patients. There are numbers of genes that are differentially expressed in chronic kidney disease which are correlated with PON gene expression including GADD45B, STK26, IFITM2///IFITM1, ZNF418, GDAP1, etc. Furthermore, iv CTS appear to be physiologic substrates for PON’s hydrolytic lactonase/2-pyronase activity and this may represent a novel regulatory mechanism for CTS. v Acknowledgements I express my deepest appreciation to my Master’s thesis adviser, Dr. David J. Kennedy for his invaluable help and guidance throughout my research work. Having him as an adviser is an honor. I also express my heartfelt thanks to my committee members, Dr. Levison Bruce and Dr. Sadik Khuder for their assistance with this thesis. Without their immense help and insightful comments this work could not be completed. My sincere thanks to Dr. Haller for useful suggestions during the research lab meetings that helped in improving this thesis. I also express my sincere thanks to my fellow labmates for stimulating ideas and discussions. It was a great fun to work in Dr. Kennedy’s lab. Finally, I express my sincere gratitude to my family for always being supportive. vi Table of Contents Abstract .............................................................................................................................. iii Acknowledgements ............................................................................................................ vi Table of Contents .............................................................................................................. vii List of Tables ......................................................................................................................x List of Figures .................................................................................................................... xi List of Abbreviations ....................................................................................................... xiii 1 Introduction ………………. ....................................................................................1 2 The Paraoxonase gene family ..................................................................................6 3 Methods 3.1 Bioinformatics approaches.................................................................................9 3.1.1 Study of PON gene expressions in different tissues in human body ..............9 3.1.2 PON genes dysregulation is related to heart and kidney disease ....................9 3.1.3 Comparison of PON gene expressions in renal biopsy samples and peripheral blood samples taken from CKD patients and non-CKD controls .....................10 3.1.4 An approach to look at the regulatory network of genes that may involve in CKD...................................................................................................................................15 3.2 Biochemical and molecular biology approaches ............................................17 3.2.1 Animal tissue culture ....................................................................................17 3.2.2 Method development to measure protein level expression of PON1 in tissue culture samples and human plasma/ serum ........................................................................19 vii 3.2.3 Method development to measure PON1 lactonase activity in human plasma and tissue culture sample ...................................................................................................24 3.2.4 Measurement of PON1 protein expression in CKD vs non-CKD human plasma…………………………………………………………………………..………. 30 3.2.5 Measurement of PON1 lactonase activity in CKD vs non-CKD human plasma…………………………………………………….………………….…………. 31 3.2.7 Measurement of PON1 protein expression in tissue culture .........................33 3.2.8 Measurement of PON1 lactonase activity in tissue culture ..........................34 3.2.9 Method development for measuring TCB by LC-MS ..................................35 3.2.10 Making Standard curve for TCB standards ................................................37 3.2.11 Measuring CTS degradation by tissue culture that produce PON1……….37 4 Results 4.1 Bioinformatics approaches...............................................................................39 4.1.1 Studying the PON genes using bioinformatics tools provided in www.ncbi.nlm.nih.gov .......................................................................................................39 4.1.2 Study of PON gene expressions in different tissue in human body ..............42 4.1.3 Comparison of PON gene expressions in renal biopsy samples and peripheral blood samples taken from CKD patients and non-CKD controls .....................44 4.1.4 An approach to look at the highly correlated genes that may involve in CKD...................…………………………………………………………………...…….46 4.2 Biochemical and molecular biology approaches .............................................51 4.2.1 Method development to measure PON1 protein expression in human plasma samples………………………………………………………………………51 viii 4.2.2 Method development to measure PON1 lactonase activity in human plasma samples…………………………………………………………………………. 51 4.2.3 Measurement of PON1 protein expression in CKD vs non-CKD human plasma……….. ......................................................................................................51 4.2.4 Measurement of PON1 lactonase activity in CKD vs non-CKD human plasma…………………………………………………….…………………...… 52 4.2.5 Measurement of PON1 protein expression in tissue culture .............52 4.2.6
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