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Effect of Ghrelin Receptor Ligands on Proliferation of Prostate Stromal Cells and on Smooth Muscle Contraction in the Human Prostate

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Effect of Ghrelin Receptor Ligands on Proliferation of Prostate Stromal Cells and on Smooth Muscle Contraction in the Human Prostate Aus der Urologischen Klinik und Poliklinik der Ludwig-Maximilians-Universität München Direktor: Prof. Dr. Christian G. Stief Effect of ghrelin receptor ligands on proliferation of prostate stromal cells and on smooth muscle contraction in the human prostate Dissertation zum Erwerb des Doktorgrades der Medizin an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Xiaolong Wang aus Wuhan, China 2020 Mit Genehmigung der Medizinischen Fakultät der Universität München Berichterstatter: Prof. Dr. rer. nat. Martin Hennenberg Mitberichterstatter: PD Dr. Heike Pohla Prof. Dr. Wolf Mutschler Dekan: Prof. Dr. med. dent. Reinhard Hickel Tag der mündlichen Prüfung: 20.02.2020 1. Introduction ........................................................................................ 1 1.1 Definition of LUTS .......................................................................... 1 1.2 Epidemiology, etiology and nature history of LUTS ................... 2 1.3 Pathogenesis of LUTS suggestive to BPH ..................................... 4 1.3.1 Age .............................................................................................. 6 1.3.2 Inflammation ............................................................................... 6 1.3.3 Sex hormones .............................................................................. 7 1.3.4. Metabolic factors ....................................................................... 7 1.3.5 Other urologic diseases associated with LUTS .......................... 9 1.3.6 Genetic determinants ................................................................ 11 1.4 The role of MetS in LUTS ............................................................ 11 1.4.1 Obesity and LUTS .................................................................... 12 1.4.2 Insulin resistance in smooth muscle ......................................... 12 1.4.3 Pro-inflammatory molecules in LUTS ..................................... 13 1.4.4 Environmental factors that contribute to LUTS ....................... 14 1.5 Pharmacological treatment for LUTS ......................................... 14 1.5.1 Monotherapy ............................................................................. 15 1.5.2 Combination therapies .............................................................. 21 1.5.3 Limits of current therapies ........................................................ 23 1.5.4 Novel compounds in pathophysiology and experimental therapy of LUTS ............................................................................................. 25 1.6 Generally studies on development of Ghrelin system ................ 28 1.6.1 History of Ghrelin ..................................................................... 28 1.6.2 Various forms ............................................................................ 29 1.6.3 Mechanisms of action ............................................................... 29 1.6.5 Major functions ......................................................................... 31 1.6.6 Role of ghrelin in disease .......................................................... 33 1.6.7 Summary ................................................................................... 34 I 1.7 Possible role of the ghrelin system in links between metabolic syndrome and LUTS suggestive to BPH ........................................... 35 1.7.1 The relationship between the metabolic syndrome and BPH/LUTS ......................................................................................... 35 1.7.2 Ghrelin system in regulation of smooth muscle tone ............... 35 1.7.3 Ghrelin system plays a role in proliferation ............................. 37 1.7.4. Ghrelin system in BPH? .......................................................... 37 2. Aims ................................................................................................... 39 3. Materials and methods .................................................................... 40 3.1 Reagents and devices ..................................................................... 40 Table 1. Reagents used in this study. ................................................. 40 Table 2: Devices used in this study. .................................................. 42 3.2 Human prostate tissues ................................................................. 42 3.3 Cell culture ..................................................................................... 43 3.4 Real time polymerase chain reaction (RT-PCR) ........................ 43 3.4.1 Reverse Transcription (RT) ...................................................... 44 Table 3: Reverse Transcription .......................................................... 44 3.4.2 Primers ...................................................................................... 44 Table 4: Primers ................................................................................. 44 3.4.3 Real-time polymerase chain reaction (RT-PCR) ...................... 45 3.5 Cell proliferation assay ................................................................. 45 3.6 Plate colony formation test ........................................................... 47 3.7 Cell cycle analysis .......................................................................... 48 3.8 Viability assay ................................................................................ 49 3.9 Tension measurements .................................................................. 50 3.10 Statistical analysis ........................................................................ 51 4. Results ............................................................................................... 53 4.1 Effects of MK-0677 on WPMY-1 cells ........................................ 53 II 4.1.1 Effects of MK-0677 on viability of WPMY-1 cells ................. 53 4.1.2 Effects of MK-0677 on proliferation of WPMY-1 cells in EdU assay ................................................................................................... 53 4.1.3 Effects of MK-0677 on proliferation of WPMY-1 cells in colony plate assay .......................................................................................... 54 4.1.4 Effects of MK-0677 on cell cycle of WPMY-1 cells ............... 55 4.2 Effect of MK-6077 on mRNA profiles of WPMY-1 cells ........... 57 4.2.1 Effects of MK0-677 on proliferation markers of WPMY-1 cells via RT-PCR ........................................................................................ 57 4.2.2 Effects of MK-0677 on cell cycle regulating factors mRNA of WPMY-1 cells ................................................................................... 57 4.2.3 Effects of MK-0677 on growth factors of WPMY-1 cells ....... 58 4.3 Effects of PF-05190457 on human prostate smooth muscle contraction ............................................................................................ 59 4.3.1 Effects on EFS-induced contractions ........................................ 59 4.3.2 Noradrenaline-induced contractions ......................................... 60 5. Discussion .......................................................................................... 62 5.1 Ghrelin and GHSR take part in proliferation and contraction in different systems .................................................................................. 63 5.2 MK-0677 enhances the proliferation of prostate cells and regulates their cell cycle. ..................................................................... 64 5.3 MK-0677 alters the profile of cell cycle regulators and growth factors ................................................................................................... 66 5.4 PF-5190457 reduced the neurogenic and adrenergic contraction of prostate tissue .................................................................................. 69 5.5 Translational aspects ..................................................................... 70 5.6 Conclusions .................................................................................... 71 III 6. Conclusion ......................................................................................... 73 7. Summary ........................................................................................... 73 8. Zusammenfassung ............................................................................ 74 9. References ......................................................................................... 76 10. Abbreviation ..................................................................................... 94 11. Acknowledgement ............................................................................ 98 12. Eidesstattliche Versicherung und Erklärung ................................ 99 IV 1. Introduction 1.1 Definition of LUTS Lower urinary tract symptoms (LUTS) are a group of symptoms related to the prostate, urethra and bladder. LUTS have three components: voiding or obstructive symptoms, storage or irritative symptoms and post-micturition symptoms [1]. The voiding symptoms include hesitancy, which means a longer wait time for the stream of urine to start, weak stream, straining during micturition, dripping after urination is over or intermittent stream. The storage symptoms include urgency (feeling an urgent need to urinate), frequency (a short interval between requirement to urinate), nocturia (have to pass urine more than two times during the night and waking from micturition),
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