Sympathoexcitation by Brain Oxidative Stress Mediates Arterial Pressure Elevation in Salt-Induced Chronic Kidney Disease

Abstract

Abstract-Hypertension is very prevalent in chronic kidney disease and critical for its prognosis. Sympathoexcitation and oxidative stress have been demonstrated to be involved in chronic kidney disease. We have shown previously that sympathoexcitation by brain oxidative stress mediates arterial pressure elevation in the salt-sensitive hypertension model, Dahl salt-sensitive rats. Thus, we investigated whether sympathoexcitation by excessive brain oxidative stress could contribute to arterial pressure elevation in salt-induced chronic kidney disease model rats. Young (3-week-old) male Sprague-Dawley rats were randomly assigned to a uninephrectomy or sham operation and then subjected to either a normal salt (0.5%) or high-salt (8.0%) diet for 4 weeks. The young salt-loaded uninephrectomized rats exhibited sympathoexcitation, hypertension, and renal injury, proteinuria and global glomerulosclerosis together with tubulointerstitial damage. Under urethane anesthesia and artificial ventilation, renal sympathetic nerve activity, arterial pressure, and heart rate decreased to a greater degree in the salt-loaded uninephrectomized rats than in the nonsalt-loaded uninephrectomized rats and the salt-loaded or nonsalt-loaded sham-operated rats, when Tempol, a membrane-permeable superoxide dismutase mimetic, was infused acutely into the lateral cerebral ventricle. Oxidative stress in the hypothalamus, measured by lucigenin chemiluminescence, was also significantly greater. Furthermore, in the salt-loaded uninephrectomized rats, antioxidant treatment with chronic intracerebroventricular Tempol decreased sympathetic nerve activity and arterial pressure, which, in turn, led to a decrease in renal damage. Similar effects were elicited by treatment with oral moxonidine, the central sympatholytic agent.

A Salt-Induced Reno-Cerebral Reflex Activates Renin-Angiotensin Systems and Promotes CKD Progression

“…Similarly, an overexpression of the brain RAS in DSS rats contributes to their hypertension, 48 whereas an inhibition of brain ROS and sympathoexcitation in salt-loaded uninephrectomized rats by tempol lessens hypertension. 49 However, the SNS, rather than hypertension, linked the brain and renal RAS because normalization of BP with hydralazine failed to prevent these responses to salt in 5/6Nx rats. Consistent with the hypothesis, salt-induced renal fibrosis and dysfunction were improved significantly in rats after central blockade of RAS or sympathetic outflow, in contrast with those treated with hydralazine.…”

Cardiovascular Autonomic Dysfunction in Chronic Kidney Disease: a Comprehensive Review

“…An inhibitory action for salt on neuronal NOS expression in the posterior hypothalamic nuclei, the locus coeruleus, and the PVN was suggested by Campese et al [150] as a possible mechanism related to the high-salt-mediated action of the SNS. A role also was proposed for brain oxidative stress in driving sympathoexcitation in response to salt load in uninephrectomized rats [151].…”

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

“…Activation of these PVN neurons can lead to sympathetic discharge (20,45). Multiple factors affect sympathetic outflow such as sodium, ANG II, glutamate, cytokines, oxidative stress, and nitric oxide (NO) (11,12,34,41,47). Previous studies have demonstrated that brain PRR activation can increase the production of inflammatory cytokines, oxidative stress, and ANG II (32,37,46).…”