Hypertension in chronic kidney disease: What lies behind the scene

FIGURE 1. Schematic representation of factors involved in kidney damage, hypertension and end-stage renal disease (ESRD). Figure shows complications arise upon activation of the renin-angiotensin system (RAS) secondary to kidney damage. Increased RAS activity subsequently activates angiotensin-1 receptor (AT1 receptors) via increasing angiotensin II (Ang II) and decreases glomerular filtration rate (GFR). Angiotensin 1 receptor activation results in a myriad of effects such as vascular remodeling and inflammation, aldosterone release, sodium/H2O retention, disturbs the balance between antioxidant (superoxide dismutase; SOD) and oxidant (nicotine amide dinucleotide phosphate; NADPH) mechanisms, and increase sympathetic nervous system (SNS) activation. A reduction in GFR causes uremia, which is associated with increased asymmetric dimethylarginine (ADMA) and oxidative stress, all of which predispose to endothelial dysfunction and loss of nitric oxide (NO) functional signaling. Impairment of the NO pathway and increased reactive oxygen species (ROS) can subsequently predispose to the aggravation of SNS activation, vascular remodeling, and inflammation, further elevating systemic hypertension.…

FIGURE 2. Surgical interventions to lower blood pressure (BP) in resistant hypertensive patients including baroreflex activation therapy (BAT) of the carotid baroreceptors and renal denervation using radiofrequency/ultrasound energy ablation of the renal nerves. Note that BAT evokes field stimulation of the baroreceptors within the carotid sinus, which increases sensory afferent traffic carried by the carotid sinus nerves to the brain. This results in reflex increases in vagal efferent outflow to the heart and decreases in sympathetic discharge to the heart and vasculature thereby reducing cardiac output and systemic vascular resistance, and ultimately BP. In renal denervation, on the other hand, the procedure eliminates both renal afferent and efferent activity including renal sympathetic nerve activity (SNA), the excessive activation of which is thought to be the driver of increased BP in hypertensive individuals. Adapted and modified from (Bhatt et al., 2019; Gajulapalli et al., 2020).

FIGURE 3. Major signaling pathways involved in endothelial and vascular smooth muscle function. Cationic amino acid transporter-y + regulates uptake of l-arginine substrate into the endothelial cell. Agent A, acting on receptor (R) of the endothelial cell activates Ca2+ influx: for example, acetylcholine (ACh) acts on the endothelial muscarinic (M3) receptor causing Ca2+ influx. The increase in intracellular Ca2+ leads to activation of endothelial nitric oxide synthase (eNOS). Shear stress or substrate supplementation of tetrahydrobiopterin (BH4) can increase activation of eNOS while the latter is inhibited by asymmetric dimethylarginine (ADMA). Nitric oxide (NO) endothelial derived relaxing factor (EDRF) then diffuses to the smooth muscle cells where it activates guanylate cyclase, which results in an increase in cyclic guanosine monophosphate (cGMP), and thus initiates processes leading to relaxation. Nω-nitro-l-arginine methyl ester (l-NAME) is a NOS inhibitor, and reactive oxygen species (ROS) act as NO scavengers. Endothelin is an endothelium-derived peptide, which causes vascular contraction via smooth muscle endothelin A and B receptors (ETA and ETB) or relaxation via endothelial…