Increased Renal Medullary Oxidative Stress Produces Hypertension

Abstract

Abstract-The present study examined whether chronic increased oxidative stress within the medulla of the kidney lowers medullary blood flow and leads to hypertension. Optical fibers were implanted into the renal cortex and medulla of uninephrectomized Sprague-Dawley rats (Harlan Sprague-Dawley, Madison, Wis) for the daily measurement of blood flow to these regions using laser-Doppler flowmetry techniques, while arterial pressure was measured from an indwelling aortic catheter. A renal medullary interstitial catheter was implanted for the continuous delivery of the superoxide dismutase (SOD) inhibitor, diethyldithiocarbamic acid (DETC), at a dose of 7.5 mg/kg/d. Renal interstitial superoxide (O 2 Ϫ ) levels were determined by perfusing an O 2 Ϫ sensitive fluorescent dye, dihydroethidium, through a microdialysis probe implanted into the medulla. Urine samples (24 hours) were collected for measurements of isoprostane excretion. The results indicate that medullary DETC infusions increased tissue O 2 Ϫ concentrations in the renal medulla (93.4Ϯ22.3,nϭ8, saline and 867.3Ϯ260.2, nϭ8, DETC; fluorescence units) and increased urinary 8-isoprostane excretion (4.1Ϯ0.4 ng/d, nϭ9, saline and 8.8Ϯ1.6 ng/d, nϭ10, DETC). Mean arterial pressure increased 24 hours after the start of intrarenal DETC infusion and remained nearly 20 mm Hg above control pressure throughout the 5 days of medullary SOD inhibition. During chronic medullary DETC infusion, medullary blood flow was significantly reduced (42.7%), whereas cortical blood flow was unchanged. Intravenous infusion of the same dose of DETC produced no changes in renal medullary or cortical blood flow or arterial blood pressure. The present experiments indicate that an increase in superoxide concentration within the renal medulla selectively reduces medullary blood flow resulting in chronic hypertension.

Hypertension as an autoimmune and inflammatory disease

“…33 In genetically hypertensive rats, the number of intrarenal superoxide-positive cells is positively correlated with systolic blood pressure levels. 14,34 Recently, resveratrol was shown to mitigate oxidative stress and normalize angiotensin signaling in the kidney and reduce blood pressure via activation of phase II antioxidant enzymes. 35 Aortic stiffening is associated with the development of hypertension.…”

The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension

“…Interstitial inflammation and angiotensin activity are also inevitably associated with oxidative stress that, in itself, is a significant influence that impairs sodium excretion. The role of oxidative stress in the renal medulla driving sodium retention has been extensively investigated by Cowley et al 67,68 Impaired pressure natriuresis and stimulated tubuloglomerular feedback have also been demonstrated in patients with hypertension. 69 The long-term effects of tubulointerstitial inflammation may also have a role in the progression of chronic renal disease.…”

Angiotensin II–NAD(P)H Oxidase–Stimulated Superoxide Modifies Tubulovascular Nitric Oxide Cross-Talk in Renal Outer Medulla

“…1 Consistent with these observations, longterm, medullary interstitial infusion of DETC led to a reduction of MBF and produced hypertension in the absence of changes in cortical blood flow. 2 Because the same dose of DETC when given intravenously neither reduced MBF nor changed arterial pressure, that study demonstrated that an increase in oxidative stress, specifically within the renal medulla, would result in hypertension.…”

“…1,2 It has been shown in short-term, anesthetized-rat studies that medullary interstitial infusion of the superoxide dismutase (SOD) inhibitor diethyldithiocarbamic acid (DETC) reduces MBF and sodium excretion without a change in blood pressure. 1 Opposite changes were observed with medullary interstitial infusion of the cellpermeable SOD mimetic 4-hydroxytetramethylpiperidine-1-oxyl (TEMPOL).…”