Cellular mediators of renal vascular dysfunction in hypertension

Abstract

Ponnuchamy B, Khalil RA. Cellular mediators of renal vascular dysfunction in hypertension. Am J Physiol Regul Integr Comp Physiol 296: R1001-R1018, 2009. First published February 18, 2009 doi:10.1152/ajpregu.90960.2008.-The renal vasculature plays a major role in the regulation of renal blood flow and the ability of the kidney to control the plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow, and consequent increase in plasma volume and has been demonstrated in several forms of hypertension (HTN), including genetic and salt-sensitive HTN. Several predisposing factors and cellular mediators have been implicated, but the relationship between their actions on the renal vasculature and the consequent effects on renal tubular function in the setting of HTN is not clearly defined. Gene mutations/ defects in an ion channel, a membrane ion transporter, and/or a regulatory enzyme in the nephron and renal vasculature may be a primary cause of renal vascular dysfunction. Environmental risk factors, such as high dietary salt intake, vascular inflammation, and oxidative stress further promote renal vascular dysfunction. Renal endothelial cell dysfunction is manifested as a decrease in the release of vasodilatory mediators, such as nitric oxide, prostacyclin, and hyperpolarizing factors, and/or an increase in vasoconstrictive mediators, such as endothelin, angiotensin II, and thromboxane A 2. Also, an increase in the amount/activity of intracellular Ca 2ϩ concentration, protein kinase C, Rho kinase, and mitogenactivated protein kinase in vascular smooth muscle promotes renal vasoconstriction. Matrix metalloproteinases and their inhibitors could also modify the composition of the extracellular matrix and lead to renal vascular remodeling. Synergistic interactions between the genetic and environmental risk factors on the cellular mediators of renal vascular dysfunction cause persistent renal vasoconstriction, increased renal vascular resistance, and decreased renal blood flow, and, consequently, lead to a disturbance in the renal control mechanisms of water and electrolyte balance, increased plasma volume, and HTN. Targeting the underlying genetic defects, environmental risk factors, and the aberrant renal vascular mediators involved should provide complementary strategies in the management of HTN. blood pressure; dietary salt; oxidative stress; cytokines; kidney; endothelium; vascular smooth muscle; extracellular matrix; matrix metalloproteinases THE ROLE OF THE KIDNEY IN the regulation of sodium and water balance and blood pressure (BP) is well recognized (53,55,128). A decrease in plasma volume and renal blood flow (RBF) stimulates renin release from the juxtaglomerular cells (JGCs) and activates the renin-angiotensin system (RAS). Renin transforms angiotensinogen to angiotensin I (ANG I), and angiotensin-converting enzyme (ACE) transforms ANG I to ANG II. ANG II stimulates the adrenal cortex to release aldosterone (Aldo), which acts on the rena...

Oxidative Stress and Hypertension: Current Concepts

“…Many mechanisms have been implicated in processes underlying oxidative stress-mediated hypertension. Of the numerous systems involved, including the central nervous system, kidney, and heart [18,19], it is probably at the level of the vasculature that ROS primarily influence blood pressure regulation. ROS are potent modulators of vascular contraction, dilatation, and structural remodeling by processes such as quenching of the vasodilator NO by O 2 − , generation of vasoconstrictor lipid peroxidation products (eg, F2-isoprostanes), depletion of tetrahydrobiopterin (a key cofactor for NO synthase), activation of proinflammatory transcription factors, stimulation of growth factor production, and induction of fibrosis through activation of matrix metalloproteinases [20, 21•, 22].…”

Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide–High Angiotensin II–Induced Cardiovascular Injury

“…For instance, MR is coupled to the nongenomic activation of the sodium channel ENaC in the renal collecting tubules (Zhou and Bubien, 2001;Lee et al, 2008;McEneaney et al, 2008), and ALDO may stimulate the surface expression and activity of the Na 1 -H 1 exchanger (NHE3) in the proximal tubules' epithelial cells (Drumm et al, 2006). Also, ENaC, NHE3, and the Na 1 -Ca 21 exchanger have been identified in VSM and endothelial cells (Golestaneh et al, 2001;Jernigan and Drummond, 2006;Ponnuchamy and Khalil, 2009), and MR may regulate the ion-gated sodium channel in endothelial cells through an effect on the cytoskeleton (Golestaneh et al, 2001). It is possible that during an HS diet, high AngII and consequent activation of MR may promote Na 1 entry into endothelial cells, and in the presence of a maximally activated Na Limitations.…”

Kidney and hypertension

“…Sem toga Ang II je stimulator TNF alfa preko makrofaga i vazokonstriktora tromboksana [74]. I na kraju, davanje Ang II utuče na formiranje superoksida što vodi smanjenju nivoa NO, vazokonstrikciji i daljem oštećenju tubulointersticijuma [75].…”