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Abstract-Superoxide radical (O 2Ϫ ) is increased in the vessel wall of spontaneously hypertensive rats (SHR) where its blockade potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of O 2 Ϫ in the hypertension and renal vasoconstriction of SHR and its interaction with nitric oxide (NO). Baseline mean arterial pressure (MAP) and renal vascular resistance were markedly elevated in SHR (nϭ6)

NADPH oxidases have a distinct cellular localization in the kidney. Reactive oxygen species (ROS) are produced in the kidney by fibroblasts, endothelial cells (EC), vascular smooth muscle cells (VSMC), mesangial cells (MCs), tubular cells, and podocyte cells. All components of the phagocytic NADPH oxidase, as well as the Nox-1 and -4, are expressed in the kidney, with a prominent expression in renal vessels, glomeruli, and podocytes, and cells of the thick ascending limb of the loop of Henle (TAL), macula densa, distal tubules, collecting ducts, and cortical interstitial fibroblasts. NADPH oxidase activity is upregulated by prolonged infusion of angiotensin II (Ang II) or a high salt diet. Since these are major factors underlying the development of hypertension, renal NADPH oxidase may have an important pathophysiological role. Indeed, recent studies with small interference RNAs (siRNAs) targeted to p22( phox ) implicate p22( phox ) in Ang II-induced activation of renal NADPH oxidase and the development of oxidative stress and hypertension, while studies with apocynin implicate activation of p47( phox ) in the development of nephropathy in a rat model of type 1 diabetes mellitus (DM). Experimental studies of the distribution, signaling, and function of NADPH oxidases in the kidney are described.

There is growing evidence that oxidative stress contributes to hypertension. Oxidative stress can precede the development of hypertension. In almost all models of hypertension, there is oxidative stress that, if corrected, lowers BP, whereas creation of oxidative stress in normal animals can cause hypertension. There is overexpression of the p22(phox) and Nox-1 components of NADPH oxidase and reduced expression of extracellular superoxide dismutase (EC-SOD) in the kidneys of ANG II-infused rodents, whereas there is overexpression of p47(phox) and gp91(phox) and reduced expression of intracellular SOD with salt loading. Several mechanisms have been identified that can make oxidative stress self-sustaining. Reactive oxygen species (ROS) can enhance afferent arteriolar tone and reactivity both indirectly via potentiation of tubuloglomerular feedback and directly by microvascular mechanisms that diminish endothelium-derived relaxation factor/nitric oxide responses, generate a cyclooxygenase-2-dependent endothelial-derived contracting factor that activates thromboxane-prostanoid receptors, and enhance vascular smooth muscle cells reactivity. ROS can diminish the efficiency with which the kidney uses O(2) for Na(+) transport and thereby diminish the P(O(2)) within the kidney cortex. This may place a break on further ROS generation yet could further enhance vasculopathy and hypertension. There is a tight relationship between oxidative stress in the kidney and the development and maintenance of hypertension.

Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80-180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca(2+)]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca(2+)]i occurs predominantly by Ca(2+) influx through L-type voltage-operated Ca(2+) channels (VOCC). Increased [Ca(2+)]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca(2+) from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca(2+) sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study.

Abstract-8-Iso prostaglandin F 2␣ (8-ISO) is formed nonenzymatically from the attack of superoxide radical on arachidonic acid. Therefore, 8-ISO is a marker of oxidative stress in vivo. We have recently shown that short-term administration of the membrane-permeable, metal-independent superoxide dismutase mimetic tempol (4-hydroxy-2, 2, 6, 6-tetramethyl piperidinoxyl) normalizes blood pressure in spontaneously hypertensive rats (SHR). The present study was designed to test whether prolonged administration of tempol ameliorates oxidative stress and hypertension in SHR. In control SHR (nϭ8), mean arterial pressure and heart rate were increased and renal blood flow and glomerular filtration rate were reduced compared with control Wistar-Kyoto rats (WKY) (nϭ7). Twenty-four-hour renal excretion of 8-ISO was significantly increased in SHR compared with WKY. Two weeks of tempol administration in the drinking water (1 mmol/L) to SHR (nϭ8) decreased mean arterial pressure by 18% (162Ϯ8 to 134Ϯ6 mm Hg, PϽ0.05), increased glomerular filtration rate by 17% (1.6Ϯ0.2 to 1.9Ϯ0.3 mL/min), and decreased renal excretion of 8-ISO by 39% (9.8Ϯ0.7 to 6.0Ϯ0.7 ng/24 hours, PϽ0.05). In contrast, tempol administration to WKY (nϭ6) had no significant effect on mean arterial pressure (115Ϯ5 versus 118Ϯ8 mm Hg), glomerular filtration rate (3.0Ϯ0.4 versus 2.5Ϯ0.5 mL/min), or renal excretion of 8-ISO (7.9Ϯ0.4 versus 6.8Ϯ0.7 ng/24 hours). In conclusion, the SHR is a model of hypertension and renal vasoconstriction associated with oxidative stress. Because long-term administration of a superoxide scavenger reduces blood pressure and oxidative stress in vivo, this study suggests a role for oxygen radicals in the maintenance of hypertension in SHR. Key Words: oxidative stress Ⅲ isoprostanes Ⅲ oxygen radicals Ⅲ superoxide dismutase R eactive oxygen species (ROS) such as superoxide anion, hydroxyl radical, and hydrogen peroxide have been implicated in atherosclerosis, diabetes, ischemia/reperfusion injury, and hypertension. [1][2][3][4] Compared with normotensive individuals, hypertensive patients have higher levels of plasma hydrogen peroxide, superoxide anion, and lipid peroxides, while having lower plasma levels of the antioxidant ascorbic acid. [5][6][7] We 8 and others 9 -12 have shown in short-term studies that inhibition of ROS reduces blood pressure in the spontaneously hypertensive rat (SHR). However, the importance of ROS in the long-term regulation of blood pressure in SHR has not been determined. Previous studies have shown increased superoxide release in mesenteric arterioles 11,12 and cultured aortic endothelial cells, 13 and increased superoxide and hydrogen peroxide release from aortic strips of SHR 14 compared with the normotensive control Wistar-Kyoto rat (WKY). These studies suggest that specific vascular beds in the SHR have oxidative stress; however, it is not yet clear whether there is a net excess of ROS in SHR in vivo.F 2 -isoprostanes are a family of prostaglandin (PG) F 2 -like compounds that are formed from the nonenzymat...

A B S T R A C T Micropuncture studies have shown that glomerular filtration rate (GFR) falls in response to a rise in Na' or Cl-concentrations in the loop of Henle, whereas studies in isolated kidneys have shown that GFR falls in response to osmotic diuresis. To define the separate effects of an acute increase in plasma sodium (PNa), chloride (Pci) or osmolality (Posmoi), changes in renal blood flow (RBF) and GFR were measured during intrarenal infusions of hypertonic NaCl, NaHCO3, Na acetate, dextrose, NH4Cl or NH4acetate to denervated kidneys. The infusions raised Posmol at the experimental kidney by [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] mosmol. RBF increased abruptly by 10-30% with all hypertonic infusions indicating that an acute increase in plasma tonicity causes renal vasodilatation. Renal vasodilatation persisted or increased further during infusion of dextrose, NaHCO3 and Na acetate, but GFR was unchanged. In contrast, during infusion of the two Clcontaining solutions, vasodilatation was reversed after 1-5 min and RBF and GFR decreased (P < 0.01) below preinfusion levels. Prior salt depletion doubled the vasoconstriction seen with hypertonic NaCl infusions. Overall, changes in RBF were unrelated to changes in PNa or fractional Na or fluid reabsorption but correlated with changes in P(:I (r = -0.91) and fractional Cl-reabsorption (r = 0.94). The intrafemoral arterial infusion of the two Cl-containing solutions did not increase femoral vascular resistance. In conclusion, hyperchloremia produces a progressive renal vasoconstriction and fall in GFR that is independent of the renal nerves, is potentiated by prior salt depletion and is related to tubular Cl-reabsorption. Chloride-induced vasoconstriction appears specific for the renal the adequacy of the extracellular volume (ECV)' is threatened by salt depletion, impaired proximal tubule reabsorption or a high perfusion pressure, renal vasoconstriction restricts the volume of filtrate delivered to the tubules (1-5). A mechanism that can relate glomerular filtration to distal fluid delivery has been identified in micropuncture experiments in which single nephron glomerular filtration rate (SNGFR) has been found to fall during a selective increase in the Na+ or Cl-concentrations or osmolality of early distal tubule fluid (6-8).In previous experiments, we (9) and others (10, 11) showed that intrarenal infusion of hypertonic NaCI solution causes transient vasodilatation followed by sustained vasoconstriction. Schnermann et al. (8) demonstrated that retrograde injection of Cl-containing solutions into the distal tubule regularly elicited a decrease in SNGFR, whereas similar injections of Nacontaining solutions did not. In contrast, in experiments on the isolated kidney, Nizet (12-14) concluded that there was no specific effect of increased Na+ or Cl-concentration on renal vascular resistance but that the GFR varied in direct proportion to tubular fluid reabsorption. To settle these differences between the responses of the isolated kidney...

Tempol is a redox cycling nitroxide that promotes the metabolism of many reactive oxygen species (ROS) and improves nitric oxide bioavailability. It has been studied extensively in animal models of oxidative stress. Tempol has been shown to preserve mitochondria against oxidative damage and improve tissue oxygenation. Tempol improved insulin responsiveness in models of diabetes mellitus and improved the dyslipidemia, reduced the weight gain and prevented diastolic dysfunction and heart failure in fat-fed models of the metabolic syndrome. Tempol protected many organs, including the heart and brain, from ischemia/reperfusion damage. Tempol prevented podocyte damage, glomerulosclerosis, proteinuria and progressive loss of renal function in models of salt and mineralocorticosteroid excess. It reduced brain or spinal cord damage after ischemia or trauma and exerted a spinal analgesic action. Tempol improved survival in several models of shock. It protected normal cells from radiation while maintaining radiation sensitivity of tumor cells. Its paradoxical pro-oxidant action in tumor cells accounted for a reduction in spontaneous tumor formation. Tempol was effective in some models of neurodegeneration. Thus, tempol has been effective in preventing several of the adverse consequences of oxidative stress and inflammation that underlie radiation damage and many of the diseases associated with aging. Indeed, tempol given from birth prolonged the life span of normal mice. However, presently tempol has been used only in human subjects as a topical agent to prevent radiation-induced alopecia.