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

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.

Aerobic Exercise Upregulates DNA Methylation of Agtr1a and Mas1 Genes to Improve Mesenteric Arterial Function in Spontaneously Hypertensive Rats

“…DNA hypermethylation is a hallmark of gene silencing, while DNA hypomethylation promotes active transcription. Recent studies have reported that methylation of Mas1/Agtra1 plays a key role in the regulation of vascular tone [25,26]. For instance, perinatal nicotine exposure enhances vascular contractility that is associated with decreased DNA methylation of Agtra1 in the aorta in adult offspring [27].…”

No answer to the lack of specificity: mouse monoclonal antibody targeting the angiotensin II type 1 receptor AT1 fails to recognize its target

“…But all tested antibodies gave signals in tissues from AT1A knock-out mice and nontransfected 4B cells. Despite this first report of aspecificity, the sc-1173 antibodies were still widely used in the literature up to now (Rizzetti et al 2018;Zhao et al 2018;Ribeiro et al 2018) and it has just been discontinued.…”

“…Polyclonal antibodies targeting both angiotensin II (AngII) receptors type 1 (AT1) and type 2 (AT2) have been described as non-specific (Benicky et al 2012;Herrera et al 2013;Hafko et al 2013). Despite these findings, antibodies directed against AT1 receptors are still widely used in the literature with more than twenty publications in 2017 using the Santa Cruz aspecific sc-1173 polyclonal antibodies (Chao et al 2017;Young et al 2017;Liu et al 2017) and already five publications in 2018 (Ahad et al 2018;Ishikane et al 2018;Rizzetti et al 2018;Zhao et al 2018;Ribeiro et al 2018).…”

Unveiling the Role of DNA Methylation in Kidney Transplantation: Novel Perspectives toward Biomarker Identification

“…In these patients, treatment with angiotensin II (Ang II) blockers for preventing or treating hypertension is closely associated with improved survival. An in vivo study demonstrated that DNA methylation modulated the recipient vascular Ang II receptor (AT1R) gene expression, which in turn increased the vascular contractility in response to Ang II [92]. Another complication in kidney transplant recipients is the new-onset diabetes after transplantation (NODAT), which increases the risk of cardiovascular disease, infections, graft loss, and mortality [93, 94].…”