Submitted on November 25, 2008
Revised on February 17, 2009
Accepted on February 17, 2009
Cellular Mediators of Renal Vascular Dysfunction in Hypertension
Bharathy Ponnuchamy1 and Raouf A. Khalil1*
1 Brigham & Women's Hospital
* To whom correspondence should be addressed. E-mail: raouf_khalil{at}hms.harvard.edu.
The renal vasculature plays a major role in the regulation of renal blood flow and the ability of kidney to control plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow and consequent increases 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 A2. Also, increased amount/activity of [Ca2+]i, protein kinase C, Rho-kinase and mitogen-activated protein kinase in vascular smooth muscle promote renal vasoconstriction. Additionally, matrix metalloproteinases and their inhibitors could 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, decreased renal blood flow, and consequently lead to 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.
