International Journal of Hypertension Table 2: Prevalence of hypertension secondary to underlying renal parenchymal disease. Acute renal failure caused by glomerular-vascular disease caused by tubulointerstitial disease Acute poststreptococcal glomerulonephritis Primary focal and segmental glomerulosclerosis Minimal-change disease Membranous glomerulonephritis Membranoproliferative glomerulonephritis Mesangial proliferative glomerulonephritis IgA nephropathy Autosomal dominant polycystic kidney disease Chronic pyelonephritis Wilms tumor Adenocarcinoma of the kidney Reﬂux nephropathy Renal tuberculosis End-stage renal disease caused by chronic glomerulonephritis caused by hypertensive nephrosclerosis caused by diabetic nephropathy 40% 73%–90% 10%–15% 60%–80% 45% nephrotic 65% non-nephrotic Rare 10% 30% 33% 25%–36% 50%–80% 33% 50% 38% 20% 4% 80%–90% 78% 100% 80% 3. Mechanisms of SNS Activation in Kidney Disease 3.1. Angiotensin II. The activation of the SNS in CKD may be related to the eﬀects of circulating angiotensin II (Ang II) released from the kidneys. We have previously shown that intracerebroventricular (ICV) infusion of Ang II raises BP, renal sympathetic nervous system activity (RSNA), and NE secretion from the PH compared to control rats. Pretreatment with losartan, an AT1 receptor blocker, given as an ICV infusion 20 min prior to the infusion of Ang II completely abolished the eﬀects of Ang II on BP, RSNA, and NE secretion from the PH [32]. Antagonists of the renin-angiotensin system, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II AT1 receptor antagonists, inhibit the produc- tion of Ang II or its ability to bind to its receptor, resulting in partial inhibition of the sympathetic nervous system in 5/6 nephrectomized rats [33], in the phenol-renal injury model [34], as well as in humans with CKD [14, 30]. 3.2. Oxidative Stress. Reactive oxygen species (ROS) are involved in the regulation of SNS activity [35]. Increased oxidative stress in key brain nuclei mediates the activation of the SNS in the phenol-renal injury model of hypertension [36] and in stroke-prone spontaneously hypertensive rats 3 [37]. Increased oxidative stress within the rostral ventral lateral medulla (RVLM) and paraventricular nucleus (PVN) was associated with hypertension and sympathetic over- activity in the 2K 1C Goldblatt model of renovascular hypertension [38], and superoxide signaling in the RVLM was found to play a major role in sustained hypertension and sympathetic nervous system activation in this model. ROS are also involved in the intracellular signaling mech- anisms of Ang II in the brain. [39, 40], in central SNS acti- vation and BP elevation in experimental models of obesity- induced hypertension [41], renovascular hypertension [38], and salt-sensitive hypertension [42]. Moreover, chronic antioxidant therapy improved oxidative stress and BP in a rat model of renovascular hypertension [38]. Despite these experimental data, antioxidants currently have no deﬁnitive role in the management of hypertension in CKD patients. 3.3. Hypoxia. Substantial evidence suggests that kidney ischemia may be responsible for sympathetic nervous system activation in renal hypertension. This is supported by studies in conscious rats with acute renal artery stenosis [21]. Restoration of renal perfusion in humans with renovascular hypertension reduces MSNA to control levels and leads to normalization of BP [43]. Regional hypoxia has also been demonstrated in polycystic kidney disease by immunostain- ing [44]. 3.4. Nitric Oxide. Recent studies have provided convincing evidence that nitric oxide synthase (NOS) is present in speciﬁc area of the brain involved in the neurogenic control of blood pressure [45, 46]. Studies on experimental animals have also provided evidence that the neuronal isoform of NOS is an important component of the transduction pathways that tonically inhibit sympathetic outﬂow from the brain stem [47–50]. In normal rats, the basal activity of the central sympathetic nervous system is regulated by local NO production. Evidence from our laboratory also indicates that local production of NO may modulate sympathetic activity in brain nuclei involved in the neurogenic regulation of BP [51]. Reduced availability of NO in these brain nuclei, may result in increased SNS activity and hypertension. 3.5. Cytokines. Complex relationships exist between SNS, nitric oxide, and cytokines [52–55]. One possible mediator for the increase in NO expression is interleukin 1β (IL- 1β). Our study has demonstrated for the ﬁrst time that administration of IL-1β in the lateral ventricle of control and CKD rats lowers BP and NE secretion from the PH [56]. Moreover, we have shown that the modulatory action of IL-1β on SNS activity is mediated by increased expression of neuronal NOS mRNA in the brain. Several lines of evidence strongly support this conclusion. First, the administration of IL-1β in the lateral ventricle of control and CKD rats caused a dose-dependent decrease in BP and NE secretion from the PH and an increase in neuronal NOS mRNA abundance in the brain nuclei. Second, infusion of a speciﬁc anti-rat IL-1β antibody in the lateral ventricle led to an elevation in BP and secretion of NE from the PH of control rats, and to a