Renal transplantation increases angiotensin II receptor-mediated vascular contractility associated with changes of epigenetic mechanisms

Zhao,Yakun; Zhu,Qingguo; Sun,Shiping; Qiu,Yu; Li,Jingquan; Liu,Wei; Yuan,Gangjun; Ma,Hua

doi:10.3892/ijmm.2018.3435

Renal transplantation increases angiotensin II receptor-mediated vascular contractility associated with changes of epigenetic mechanisms

Authors:
- Yakun Zhao
- Qingguo Zhu
- Shiping Sun
- Yu Qiu
- Jingquan Li
- Wei Liu
- Gangjun Yuan
- Hua Ma
View Affiliations

Affiliations: Department of Urinary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China, Surgical Department, The People's Hospital of Fuyun County, Aletai, Xinjiang 836100, P.R. China
Published online on: January 29, 2018 https://doi.org/10.3892/ijmm.2018.3435
Pages: 2375-2388

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hypertension is one of the most common complications following renal transplantation, and it increases the risk of graft loss and other cardiovascular diseases. Previous studies have revealed that the use of angiotensin II (Ang II) blockers for preventing and treating hypertension is closely associated with higher survival following renal transplantation. However, the cellular and molecular mechanisms by which the vascular contractility of the recipient is altered in response to Ang II following renal transplantation have not been fully elucidated. In the present study, using the Fisher‑Lewis rat kidney transplantation model, the blood pressure (BP) of the conscious transplant recipient was measured following the intravenous administration of Ang II. In addition, the mechanisms underlying the Ang II-mediated vascular contractility via the type 1 and type 2 Ang II receptors (AT1R and AT2R, respectively) in large and small-resistance blood vessels were determined in the recipient after renal transplantation. The results showed that renal transplantation significantly increased the Ang II-stimulated BP of the rats. Additionally, ex vivo contractility experiments using aorta and mesenteric arteries revealed that the contractions induced by Ang II were significantly strengthened in the recipient following renal transplantation, and were associated with an increased intracellular Ca2+ concentration. Losartan almost eradicated the Ang II-induced contractions whereas PD-123319 had no apparent effects on the Ang II-induced contractions in the aorta and mesenteric arteries of the recipient. Furthermore, the expression levels of AT1R but not AT2R were significantly increased in the vasculature of the recipient following renal transplantation, which exhibited a close association with selective DNA demethylation detected in the promoter region of the vascular AT1aR gene. These results indicate that changes of recipient vascular AT1R gene expression, occurring through a mechanism involving DNA methylation, increase the vascular contractility in response to Ang II. This may lead to the increased risk of hypertension following renal transplantation.

View Figures

View References

1	Chandran S and Vincenti F: Clinical aspects: Focusing on key unique organ-specific issues of renal transplantation. Cold Spring Harb Perspect Med. 4:42014. View Article : Google Scholar
2	Lyerová L, Viklický O, Nemcová D and Teplan V: The incidence of infectious diseases after renal transplantation: A single-centre experience. Int J Antimicrob Agents. 31(Suppl 1): S58–S62. 2008. View Article : Google Scholar
3	Saidi RF and Hejazii Kenari SK: Clinical transplantation and tolerance: Are we there yet? Int J Organ Transplant Med. 5:137–145. 2014.PubMed/NCBI
4	Holmberg C and Jalanko H: Long-term effects of paediatric kidney transplantation. Nat Rev Nephrol. 12:301–311. 2016. View Article : Google Scholar
5	Mitsnefes MM, Khoury PR and McEnery PT: Early post-transplantation hypertension and poor long-term renal allograft survival in pediatric patients. J Pediatr. 143:98–103. 2003. View Article : Google Scholar : PubMed/NCBI
6	Stoumpos S, Jardine AG and Mark PB: Cardiovascular morbidity and mortality after kidney transplantation. Transpl Int. 28:10–21. 2015. View Article : Google Scholar
7	Briese S, Claus M and Querfeld U: Arterial stiffness in children after renal transplantation. Pediatr Nephrol. 23:2241–2245. 2008. View Article : Google Scholar : PubMed/NCBI
8	Cseprekál O, Kis E, Dégi AA, Kerti A, Szabó AJ and Reusz GS: Bone metabolism and arterial stiffness after renal transplantation. Kidney Blood Press Res. 39:507–515. 2014. View Article : Google Scholar : PubMed/NCBI
9	Harrison-Bernard LM: The renal renin-angiotensin system. Adv Physiol Educ. 33:270–274. 2009. View Article : Google Scholar : PubMed/NCBI
10	Paul M, Poyan Mehr A and Kreutz R: Physiology of local renin-angiotensin systems. Physiol Rev. 86:747–803. 2006. View Article : Google Scholar : PubMed/NCBI
11	Mehta PK and Griendling KK: Angiotensin II cell signaling: Physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol. 292:C82–C97. 2007. View Article : Google Scholar
12	Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S, Vanderheyden PM and Thomas WG: International Union of Basic and Clinical Pharmacology. XCIX Angiotensin receptors: Interpreters of pathophysiological angiotensinergic stimuli [corrected] Pharmacol Rev. 67:754–819. 2015.
13	de Gasparo M, Catt KJ, Inagami T, Wright JW and Unger T: International union of pharmacology. XXIII The angiotensin II receptors Pharmacol Rev. 52:415–472. 2000.
14	van Thiel BS, van der Pluijm I, te Riet L, Essers J and Danser AH: The renin-angiotensin system and its involvement in vascular disease. Eur J Pharmacol. 763:3–14. 2015. View Article : Google Scholar : PubMed/NCBI
15	Gabriëls G, August C, Grisk O, Steinmetz M, Kosch M, Rahn KH and Schlatter E: Impact of renal transplantation on small vessel reactivity. Transplantation. 75:689–697. 2003. View Article : Google Scholar : PubMed/NCBI
16	Formica RN Jr, Friedman AL, Lorber MI, Smith JD, Eisen T and Bia MJ: A randomized trial comparing losartan with amlodipine as initial therapy for hypertension in the early post-transplant period. Nephrol Dial Transplant. 21:1389–1394. 2006. View Article : Google Scholar : PubMed/NCBI
17	Pilmore HL, Skeans MA, Snyder JJ, Israni AK and Kasiske BL: Cardiovascular disease medications after renal transplantation: Results from the patient outcomes in renal transplantation study. Transplantation. 91:542–551. 2011. View Article : Google Scholar : PubMed/NCBI
18	Goldberg AD, Allis CD and Bernstein E: Epigenetics: A landscape takes shape. Cell. 128:635–638. 2007. View Article : Google Scholar : PubMed/NCBI
19	Zoghbi HY and Beaudet AL: Epigenetics and human disease. Cold Spring Harb Perspect Biol. 8:a0194972016. View Article : Google Scholar : PubMed/NCBI
20	Mas VR, Le TH and Maluf DG: Epigenetics in kidney transplantation: Current evidence, predictions, and future research directions. Transplantation. 100:23–38. 2016. View Article : Google Scholar
21	Bontha SV, Maluf DG, Mueller TF and Mas VR: Systems biology in kidney transplantation: The application of multi-omics to a complex model. Am J Transplant. 17:11–21. 2017. View Article : Google Scholar
22	Kim JI, Jung KJ, Jang HS and Park KM: Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury. Am J Physiol Renal Physiol. 305:F61–F70. 2013. View Article : Google Scholar : PubMed/NCBI
23	Sui W, Lin H, Peng W, Huang Y, Chen J, Zhang Y and Dai Y: Molecular dysfunctions in acute rejection after renal transplantation revealed by integrated analysis of transcription factor, microRNA and long noncoding RNA. Genomics. 102:310–322. 2013. View Article : Google Scholar : PubMed/NCBI
24	Betts G, Shankar S, Sherston S, Friend P and Wood KJ: Examination of serum miRNA levels in kidney transplant recipients with acute rejection. Transplantation. 97:e28–e30. 2014. View Article : Google Scholar : PubMed/NCBI
25	Becker-Cohen R, Nir A, Rinat C, Feinstein S, Algur N, Farber B and Frishberg Y: Risk factors for cardiovascular disease in children and young adults after renal transplantation. Clin J Am Soc Nephrol. 1:1284–1292. 2006. View Article : Google Scholar
26	Baumann M, Chang J, Thürmel K, Roos M, von Eynatten M, Sollinger D, Lutz J and Heemann U: Fisher-Lewis kidney transplantation model as a tool for investigation of transplantation-induced cardiomyopathy. Transplant Proc. 41:2612–2615. 2009. View Article : Google Scholar : PubMed/NCBI
27	Xiao D, Xu Z, Huang X, Longo LD, Yang S and Zhang L: Prenatal gender-related nicotine exposure increases blood pressure response to angiotensin II in adult offspring. Hypertension. 51:1239–1247. 2008. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
29	Gasc JM, Shanmugam S, Sibony M and Corvol P: Tissue-specific expression of type 1 angiotensin II receptor subtypes. An in situ hybridization study Hypertension. 24:531–537. 1994.
30	Bulum B, Ozcakar ZB, Kavaz A, Tutar E, Ekim M and Yalcinkaya F: Hypertension in children after renal transplantation. Pediatr Int. 57:1138–1142. 2015. View Article : Google Scholar : PubMed/NCBI
31	Weir MR, Burgess ED, Cooper JE, Fenves AZ, Goldsmith D, McKay D, Mehrotra A, Mitsnefes MM, Sica DA and Taler SJ: Assessment and management of hypertension in transplant patients. J Am Soc Nephrol. 26:1248–1260. 2015. View Article : Google Scholar : PubMed/NCBI
32	Chatzikyrkou C, Eichler J, Karch A, Clajus C, Scurt FG, Ramackers W, Lehner F, Menne J, Haller H, Mertens PR, et al: Short- and long-term effects of the use of RAAS blockers immediately after renal transplantation. Blood Press. 26:30–38. 2017. View Article : Google Scholar
33	Reudelhuber TL: The renin-angiotensin system: Peptides and enzymes beyond angiotensin II. Curr Opin Nephrol Hypertens. 14:155–159. 2005. View Article : Google Scholar : PubMed/NCBI
34	Steckelings UM, Rompe F, Kaschina E and Unger T: The evolving story of the RAAS in hypertension, diabetes and CV disease: Moving from macrovascular to microvascular targets. Fundam Clin Pharmacol. 23:693–703. 2009. View Article : Google Scholar : PubMed/NCBI
35	Rizzoni D, De Ciuceis C, Salvetti M, Paini A, Rossini C, Agabiti-Rosei C and Muiesan ML: Interactions between macro- and micro-circulation: Are they relevant? High Blood Press Cardiovasc Prev. 22:119–128. 2015. View Article : Google Scholar : PubMed/NCBI
36	Kaplan NM and Victor RG: Primary hypertension: Pathogenesis (with a special section on renal denervation and carotid barorecptor pacing). Kaplan's Clinical Hypertension. 11th edition. Williams and Wilkins; Philadelphia, PA: pp. 40–115. 2014
37	Triggle CR, Samuel SM, Ravishankar S, Marei I, Arunachalam G and Ding H: The endothelium: Influencing vascular smooth muscle in many ways. Can J Physiol Pharmacol. 90:713–738. 2012. View Article : Google Scholar : PubMed/NCBI
38	Kang KT: Endothelium-derived relaxing factors of small resistance arteries in hypertension. Toxicol Res. 30:141–148. 2014. View Article : Google Scholar : PubMed/NCBI
39	Touyz RM and Schiffrin EL: Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev. 52:639–672. 2000.PubMed/NCBI
40	Horowitz A, Menice CB, Laporte R and Morgan KG: Mechanisms of smooth muscle contraction. Physiol Rev. 76:967–1003. 1996. View Article : Google Scholar : PubMed/NCBI
41	Perez-Vizcaino F, Cogolludo A and Moreno L: Reactive oxygen species signaling in pulmonary vascular smooth muscle. Respir Physiol Neurobiol. 174:212–220. 2010. View Article : Google Scholar : PubMed/NCBI
42	Hansen PB: The complex field of interplay between vasoactive agents. Kidney Int. 76:929–931. 2009. View Article : Google Scholar : PubMed/NCBI
43	Beevers DG, Morton JJ, Nelson CS, Padfield PL, Titterington M and Tree M: Angiotensin II in essential hypertension. Br Med J. 1:4151977. View Article : Google Scholar : PubMed/NCBI
44	Morton JJ, Garcia del Rio C and Hughes MJ: Effect of acute vasopressin infusion on blood pressure and plasma angiotensin II in normotensive and DOCA-salt hypertensive rats. Clin Sci (Lond). 62:143–149. 1982. View Article : Google Scholar
45	Campbell DJ: Angiotensin II generation in vivo: Does it involve enzymes other than renin and angiotensin-converting enzyme? J Renin Angiotensin Aldosterone Syst. 13:314–316. 2012. View Article : Google Scholar : PubMed/NCBI
46	Kakar SS, Sellers JC, Devor DC, Musgrove LC and Neill JD: Angiotensin II type-1 receptor subtype cDNAs: Differential tissue expression and hormonal regulation. Biochem Biophys Res Commun. 183:1090–1096. 1992. View Article : Google Scholar : PubMed/NCBI
47	Millis RM: Epigenetics and hypertension. Curr Hypertens Rep. 13:21–28. 2011. View Article : Google Scholar
48	Deaton AM and Bird A: CpG islands and the regulation of transcription. Genes Dev. 25:1010–1022. 2011. View Article : Google Scholar : PubMed/NCBI
49	Jones PA: Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat Rev Genet. 13:484–492. 2012. View Article : Google Scholar : PubMed/NCBI
50	Xiao D, Dasgupta C, Li Y, Huang X and Zhang L: Perinatal nicotine exposure increases angiotensin II receptor-mediated vascular contractility in adult offspring. PLoS One. 9:e1081612014. View Article : Google Scholar : PubMed/NCBI
51	Haack KK, Mitra AK and Zucker IH: NF-κB and CREB are required for angiotensin II type 1 receptor upregulation in neurons. PLoS One. 8:e786952013. View Article : Google Scholar
52	Nickenig G, Strehlow K, Wassmann S, Bäumer AT, Albory K, Sauer H and Böhm M: Differential effects of estrogen and progesterone on AT(1) receptor gene expression in vascular smooth muscle cells. Circulation. 102:1828–1833. 2000. View Article : Google Scholar : PubMed/NCBI
53	Wenger NK, Speroff L and Packard B: Cardiovascular health and disease in women. N Engl J Med. 329:247–256. 1993. View Article : Google Scholar : PubMed/NCBI
54	Miller VM and Duckles SP: Vascular actions of estrogens: Functional implications. Pharmacol Rev. 60:210–241. 2008. View Article : Google Scholar : PubMed/NCBI
55	El-Mas MM and Abdel-Rahman AA: Longitudinal assessment of the effects of oestrogen on blood pressure and cardiovascular autonomic activity in female rats. Clin Exp Pharmacol Physiol. 36:1002–1009. 2009. View Article : Google Scholar : PubMed/NCBI