133Endothelins
Endothelins are produced primarily by cells of the vascular endothelium and col-
lecting tubules. Endothelin-1 exerts a wide range of biologic effects in the kidney
and is involved in normal renal function, modulating glomerular filtration rate, and
solute and water reabsorption along the nephron. Besides these modulating effects,
increased endothelin-1 levels are known to cause hypertension, inflammation, and
glomerular and tubulointerstitial fibrosis [ 30 ]. During the course of CKD, the intra-
renal synthesis of endothelin-1 is remarkably upregulated, and high level of endo-
thelin- 1 has been reported in both hypertensive and CKD patients [ 30 ]. Locally
produced and released endothelin-1 not only causes constriction of most renal ves-
sels but also causes inappropriate sodium and water retention. Impaired renal clear-
ance of endothelin-1 may cause hypertension in CKD patients. In addition to its
contractile actions on vascular smooth muscle, endothelins can also modulate SNS
activity.
Nitric Oxide
NO plays a prominent role in the homeostatic regulation and integration of glo-
merular, vascular, and tubular function in the kidney [ 32 ]. Processes that can impair
the release of NO or that reduce the bioavailability of NO impair an important vaso-
dilatory response. CKD is a state of NO deficiency secondary to decreased NO
production and/or increased bioinactivation of NO by reactive oxygen species [ 33 ].
Moreover, CKD leads to the accumulation of endogenous NO synthase inhibitors
such as asymmetric dimethylarginine. Chronic inhibition of NO synthases promotes
an increase in blood pressure and vasculopathy. Altered nitric oxide/endothelin bal-
ance further increases the blood pressure rising effects of these humoral factors.
Renalase
Renalase is the only known amine oxidase that metabolizes circulating catechol-
amines [ 34 ]. The kidney appears to be the major source of circulating renalase.
Blood renalase concentration was found lower in patients with severe kidney dis-
ease, as compared with healthy subjects [ 34 ]. There may be a causal link between
decreased renalase levels and increased dopamine and norepinephrine levels in
patients with ESRD [ 34 ]. Recent evidences suggest that renalase lowers blood pres-
sure and heart rate by metabolizing circulating catecholamines [ 35 ]. Abnormalities
in the renalase pathway seem to contribute to the CKD-related hypertension.
8 Pathophysiological Insights of Hypertension in Patients with Chronic Kidney Disease