In Silico Analysis of Human AGTR1 Gene and Precision Medicine Among Hypertensive Population
Renin-angiotensin-aldosterone system (RAAS) is the most important regulator of blood pressure to maintain homeostasis and vascular tone. The effect is mediated by four primary genes: angiotensinogen (AGT), renin (REN), angiotensin-I-converting enzyme (ACE
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In Silico Analysis of Human AGTR1 Gene and Precision Medicine Among Hypertensive Population Praveen P. Balgir and Jaspreet Kaur
4.1
Introduction
4.1.1 Renin-Angiotensin-Aldosterone System (RAAS) Pathway RAAS is critical to the control of blood pressure and is the target of several types of antihypertensive drugs. RAAS pathway (Fig. 4.1) depicts the pharmacodynamics (PD) of RAAS-regulating drugs including candidate genes for the pharmacogenetics (PGx) of ACE inhibitors, angiotensin receptor blockers (ARBs), and rennin inhibitor aliskiren and aldosterone receptor antagonists. RAAS involves the conversion of angiotensinogen to angiotensin I (Ang I) by renin and its subsequent conversion to angiotensin II (Ang II) by angiotensin- converting enzyme (ACE). Ang II activates the angiotensin II receptor type 1 (AT1) to induce aldosterone synthesis, increasing water and salt resorption and potassium excretion in the kidney with resultant increase in blood pressure (Weir 2007). ACE inhibitors target the ACE protein by binding to the Zn2+ contained in the ACE enzyme and block the conversion of angiotensin I into angiotensin II. This results in downstream reduction of Ang II, decreasing aldosterone secretion and reducing blood pressure. The antihypertensive activity of the ACE inhibitors is due to various effects. Firstly, inhibition of angiotensin II at both systemic and tissue levels leads to reduction in plasma aldosterone together with vasodilatation, resulting in increased natriuresis and diuresis. Secondly, Since ACE is identical to kininase II (responsible for the breakdown of bradykinin), the inhibition of this enzyme leads to an increase in the circulating levels of bradykinin, which in turn causes peripheral vasodilatation. It also stimulates the secretion of prostaglandins (PGE2, PGI2), which induce vasodilation. The ACE inhibitors have an inhibitory effect on the release of
P. P. Balgir (*) · J. Kaur Department of Biotechnology, Punjabi University, Patiala, Punjab, India © Springer Nature Singapore Pte Ltd. 2018 S. K. Gahlawat et al. (eds.), Advances in Animal Biotechnology and its Applications, https://doi.org/10.1007/978-981-10-4702-2_4
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P. P. Balgir and J. Kaur Inhibitory signal/Down-regulation Stimulatory Signal ACE Inhibitors
Na and water Retention, K+ Excretion
ACE
Liver Angiotensinogen
Decrease in Renal Perfusion
CNS Stimulation
Angiotensin I
Renin From Kidneys
Aliskiren
Angiotensin II
AT1R
Aldosterone Release
ARBs AT2R Vasodilation, Apoptosis Anti-inflammation, Anti-fibrosis
Increase in Blood Pressure
Vasoconstriction and hypertrophy ADH Secretion, Effective circulating volume increases,
Fig. 4.1 Showing the RAAS pathway. (Adapted from KEGG pathways) (AT1R Angiotensin type 1 receptor, AT2R Angiotensin type 2 receptor, ARBs Angiotensin receptor blockers, Renin = Inhibitory Signal, = Stimulatory Signal Inhibitors, CNS Central Nervous System).
antidiuretic hormone (ADH) and reduce both central and peripheral sympathetic nervous system activity. The ARBs represent a relatively
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