Renin-angiotensin and kallikrein-kinin systems: a significance in the benign prostatic hyperplasia pathogenesis

Background. Benign prostatic hyperplasia (BPH) is the most common disease in older men. BPH pathophysiology is poorly understood. Although, it is known that the transmission of androgenergic signals and the reactivity of prostate's stroma as well as inflammatory factors are known to be the main pathophysiological mechanisms. In this regard, it is of interest to study the activity of enzymes and their inhibitors of the renin-angiotensin and kallikrein-kinin systems in BPH.

Objectives. The study of new molecular mechanisms of the BPH pathogenesis.

Materials and methods. The activity of the angiotensin-converting enzyme (ACE), the kallikrein-like activity and the prekallikrein content were determined. The total arginine-esterase activity was the inhibitory activity of the a1-proteinase inhibitor and a2-macroglobulin in the prostate secretion in men with BPH.

A sharp increase of ACE activity in BPH leads to the accumulation of angiotensin II in the prostate secretion. A consequence of the activation of ACE in prostate secretion is a decrease in the content of bradykinin. An increase of the a1-proteinase inhibitor suppressing activity in prostate secretion at BPH indicates an increase in leukocyte degranulation activity during the development of the inflammatory process.

Results. A sharp increase of ACE activity in BPH leads to the accumulation of angiotensin II in the prostate secretion. A consequence of the activation of ACE in prostate secretion is a decrease in the content of bradykinin. An increase of the a1-proteinase inhibitor suppressing activity in prostate secretion at BPH indicates an increase in leukocyte degranulation activity during the development of the inflammatory process.

Conclusion. Metabolic basis for the BPH development can be mediated by impaired metathesis of angiotensin II and bradykinin in the prostate.

1. Chapple CR, Wein AJ, Abrams P, Dmochowski RR, Giuliano F, Kaplan SA, McVary KT, Roehrborn CG. Lower urinary tract symptoms revisited: a broader clinical perspective. Eur Urol. 2008;54(3):563-56. DOI: 10.1016/j.eururo.2008.03.109

2. Gharaee-Kermani M, Kasina S, Moore BB, Thomas D, Mehra R, Macoska JA. CXC-type chemokines promote myofibroblast phenoconversion and prostatic fibrosis. PLoS One. 2012;7(11):e49278.23. DOI: 10.1371/journal.pone.0049278

3. Vignozzi L, Gacci M, Cellai I, Santi R, Corona G, Morelli A, Rastrelli G, Comeglio P, Sebastanelli A, Maneschi E, Nesi G, De Nunzio C, Tubaro A, Mannucci E, Carini M, Maggi M. Fat boosts, while androgen receptor activation counteracts, BPH-associated prostate inflammation. Prostate. 2013;73(8):789-800. DOI: 10.1002/pros.22623

4. Middleton LW, Shen Z, Varma S, Pollack AS, Gong X, Zhu S, Zhu C, Foley JW, Vennam S, Sweeney RT, Tu K, Biscocho J, Eminaga O, Nolley R, Tibshirani R, Brooks JD, West RB, Pollack JR. Genomic analysis of benign prostatic hyperplasia implicates cellular re-landscaping in disease pathogenesis. JCI Insight. 2019;4(12):e129749. DOI: 10.1172/jci.in-sight.129749

5. Kogan MI, Chernogubova EA, Chibichyan MB, Matishov DG. The activity of proteolytic enzymes and their inhibitors in the secreti on of the prostate in its benign hyperplasia and cancer. Oncourology. 2011;7(2):46-51. (In Russ.) DOI: 10.17650/1726-9776-2011-7-2-46-51

6. Kogan MI, Chernogubova EA, Chibichjan MB, Macionis AJe, Povilajtite PJe, Matishov D.G. The role of kallikrein-kinin and renin-angiotensin system in the pathogenesis of prostate cancer. Urologii. 2015. 2015;3:50-54. (In Russ.)

7. Chibichyan MB, Kogan MI, Chernogubova EA, Pavlenko IA, Matishov DG. Role of angiotensin ii receptor type 2 in predicting biochemical recurrence in the treatment of prostate cancer. Urologii. 2016; 3:89-94. (In Russ.)

8. Kogan MI Chernogubova EA, Chibichyan MB, Matishov DG. Angiotensin converting enzyme - a new prognostic marker of recurrence in the treatment of prostate cancer. Oncourol-ogy. 2016;12(2):46-51. (In Russ.) DOI: 10.17650/1726-9776-2016-12-4-87-93

9. Gorbunova EN, Davydova DA, Krupin VN. Chronic inflammation and fibrosis as risk factors for prostatic intraepithelial neoplasms and prostate cancer. Sovrem tehnol med. 2011;(1):79-83. (In Russ.)

10. GOST R 52379-2005 The nati onal standard of the Russian Federation "Good Clinical Practice" (GCP), (approved by the order of the Federal Agency for Technical Regulation and Metrology of September 27, 2005 N 232-st. Available at: http://docs.cntd.ru/document/1200041147 Accessed July 06, 2018 (In Russ.)

11. Yarovaya GA, Neshkova AE. Kallikrein-kinin system. Past and present. (to the 90th anniversary of the opening of the system) Bioorganicheskaya khimiya. 2015; 41(3): 275-291. (In Russ.). DOI: 10.7868/S0132342315030112

12. Paskhina TS, Krinskaya AV. A simplified method for determining kallikreinogen and kallikrein in the serum (plasma) of human blood in normal and under certain pathological conditions. Voprosy meditsinskoi khimii. 1974; 20(6): 660663 (In Russ.)

13. Paskhina, TS, Yarovaya GA. Kallikrein of human blood serum. Enzyme activity and chromatographic method of determination. Biokhimiya. 1970;35(5): 1055-1058. (In Russ.)

14. Nartikova VF, Paskhina TS. A method for estimation of a1-antitrypsin and of a2-macroglobulin in human blood serum (plasma) in normal state and under some pathological conditions. Voprosy meditsinskoi khimii. 1979; 25(4):494-499 (In Russ.)

15. Dotsenko VL, Neshkova EA, Iarovaia GA. Detection of human leukocyte elastase from a plasma a1-proteinase inhibitor complex by its enzymatic activity with synthetic substrate. Voprosy meditsinskoi khimii. 1994;40(3):20-25 (In Russ.)

16. Parfenkova GA, Ogloblina OG, Domba GYu. The clinical significance of determining the activity of elastase and chem-riptin-like proteinases in plasma of patients with nonspecific aortoarteritis and atherosclerosis. Kardiologiya. 1989;9:94-96. (In Russ.)

17. Rebrova OYu. Statistical analysis of medical data. Application of the STATISTICA applied programs package. Moscow: MediaSphera Press; 2002.

18. Chibichyan MB, Matsionis AE, Povilaitite PE, Kogan MI. Role of the kallikrein-kinin receptor system in prostatic proliferative processes. Oncourologi. 2013;(1):43-50. (in Russ.)

19. Leeb-Lundberg LM, Marceau F, Muller-Esterl W, Peffibone DJ, Zuraw BL. Internati onal union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev. 2005;57:27-77. DOI: 10.1124/pr.57.1.2

20. Srinivasan D, Kosaka AH, Daniels DV, Ford AP, Bhattacharya A. Pharmacological and functional characterization of bradykinin B2 receptor in human prostate. Eur J Pharmacol. 2004;504(3):155-67. PMID: 15541417

21. Bernstein KE, Ong FS, Blackwell WL, Shah KH, Giani JF, Gonzalez-Villalobos RA, Shen XZ, Fuchs S, Touyz RM. A modern understanding of the traditional and nontraditional biological functions of Angiotensin-converting enzyme. Pharmacol Rev. 2013:65: 1-46. DOI: 10.1124/pr.112.006809

22. Kryukova OV, Tikhomirova VE, Golukhova EZ, Evdokimov VV, Kalantarov GF, Trakht IN, Schwartz DE, Dull RO, Gusakov AV, Uporov IV, Kost OA, Danilov SM. Tissue Specificity of Human Angiotensin I-Converting Enzyme. PLoS One. 2015;10(11):e0143455. DOI: 10.1371/journal.pone.0143455

23. Dinh DT, Frauman AG, Somers GR, Ohishi M, Zhou J, Casley DJ, Johnston CI, Fabiani ME. Evidence for activation of the renin-angiotensin system in the human prostate: increased angiotensin II and reduced AT(1) receptor expression in benign prostatic hyperplasia. J Pathol. 2002;196(2):213-9. DOI: 10.1002/path.1021

24. Fabiani ME, Sourial M, Thomas WG, Johnston CI, Johnston CI, Frauman AG. Angiotensin II enhances noradrenaline release from sympathetic nerves of the rat prostate via a novel angiotensin receptor: implications for the pathophysiology of benign prostatic hyperplasia. J Endocrinol. 2001;171(1):97-108. PMID: 11572794

25. Kwon CH, Park HJ, Lee JR, Kim HK, Jeon TY, Jo HJ, Kim DH, Kim GH, Park DY. Serpin peptidase inhibitor clade a member 1 is a biomarker of poor prognosis in gastric cancer. Br J Cancer. 2014:111:1993-2002. DOI: 10.1038/bjc.2014.490

26. Zhao W, Yang Z, Liu X, Tian Q, Lv Y, Liang Y, Li C, Gao X, Chen L. Identification of a1-antitrypsin as a potential prognostic biomarker for advanced nonsmall cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors by proteomic analysis. J Int Med Res. 2013;41:573-583. DOI: 10.1177/0300060513476582

27. Kuvibidila S, Rayford W. Correlation between serum prostate-specific antigen and alpha-1-antitrypsin in men without and with prostate cancer. J Lab Clin Med. 2006;147(4):174-81. PMCID 16581345

28. Zhang WM, Finne P, Leinonen J, Stenman UH. Characterization and determination of the complex between prostate-specific antigen and a1-protease inhibitor in benign and malignant prostatic diseases. Scand J Clin Lab Invest Suppl. 2000;60(233):51-58. DOI: 10.1080/clb.60.233.51.58

29. Kostova MB, Brennen WN, Lopez D, Anthony L, Wang H, Platz E, Denmeade SR. PSA-alpha-2-macroglobulin complex is enzymatically active in the serum of patients with advanced prostate cancer and can degrade circulating peptide hormones. Prostate. 2018;78(11):819-829. DOI: 10.1002/pros.23539

30. Zorin NA, Zorina VN, Zorina RM. Universal modulator of cytokines a2-macroglobulin. Immunologiya. 2004; 25(5): 302-304. (In Russ.)

31. Geffins PG. Serpin structure, mechanism, and function. Chem. Rev. 2002;102(12):4751-4804. DOI: 10.1021/cr010170