Role of extracellular superoxide dismutase in the mouse angiotensin slow pressor response.
ABSTRACT Low rates of angiotensin II (Ang II) infusion raise blood pressure, renal vascular resistance (RVR), NADPH oxidase activity, and superoxide. We tested the hypothesis that these effects are ameliorated by extracellular superoxide dismutase (EC-SOD). EC-SOD knockout (-/-) and wild type (+/+) mice were equipped with blood pressure telemeters and infused subcutaneously with Ang II (400 ng/kg per minute) or vehicle for 2 weeks. During vehicle infusion, EC-SOD -/- mice had significantly (P<0.05) higher MAP (+/+: 107+/-3 mm Hg versus -/-: 114+/-2 mm Hg; n=11 to 14), RVR, lipid peroxidation, renal cortical p22(phox) expression, and NADPH oxidase activity. Ang II infusion in EC-SOD +/+ mice significantly (P<0.05) increased MAP, RVR, p22(phox), NADPH oxidase activity, and lipid peroxidation. Ang II reduced SOD activity in plasma, aorta, and kidney accompanied by reduced renal EC-SOD expression. During Ang II infusion, both groups had similar values for MAP (+/+ Ang II: 125+/-3 versus -/- Ang II: 124+/-3 mmHg; P value not significant), RVR, NADPH oxidase activity, and lipid peroxidation. SOD activity in the kidneys of Ang II-infused mice was paradoxically higher in EC-SOD -/- mice (+/+: 8.8+/-1.2 U/mg protein(-1) versus -/-: 13.7+/-1.6 U/mg protein(-1); P<0.05) accompanied by a significant upregulation of mRNA and protein for Cu/Zn-SOD. In conclusion, EC-SOD protects normal mice against oxidative stress by attenuating renal p22(phox) expression, NADPH oxidase activation, and the accompanying renal vasoconstriction and hypertension. However, during an Ang II slow pressor response, renal EC-SOD expression is reduced and, in its absence, renal Cu/Zn-SOD is upregulated and may prevent excessive Ang II-induced renal oxidative stress, renal vasoconstriction, and hypertension.
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ABSTRACT: Hyperhomocysteinemia is an independent risk factor for atherosclerosis. Homocysteine has been shown to induce endoplasmic reticulum (ER) stress in vascular endothelial cells. ER stress is a condition in which glycoprotein trafficking is disrupted and unfolded proteins accumulate in the ER. ER molecular chaperons, such as GRP78, are induced and an ER resident kinase, PERK, is activated when cells are subjected to ER stress. Conversely, taurine is reported to have antiatherogenic effects by unknown mechanisms. To elucidate the mechanisms by which homocysteine induces atherosclerosis and taurine prevents it, we examined whether homocysteine and taurine affect the expression and secretion of extracellular superoxide dismutase (EC-SOD), a glycoprotein secreted from vascular smooth muscle cells (VSMCs) that protects the vascular wall from oxidative stress. We assessed the expression of EC-SOD and GRP78 mRNA in cultured rat VSMCs by Northern blot analysis. The EC-SOD protein secreted into the culture medium was examined by Western blot analysis. Homocysteine (5 mmol/L) and other ER stress inducers, including A23187, were found to decrease EC-SOD mRNA expression and protein secretion. Furthermore, they upregulated GRP78 mRNA expression and activated PERK. Taurine (0.5 to 10 mmol/L), conversely, prevented these actions induced by homocysteine. Homocysteine induces ER stress and reduces the secretion and expression of EC-SOD in VSMCs, leading to increased oxidative stress in the vascular wall. Taurine restores the secretion and expression of EC-SOD by ameliorating ER stress induced by homocysteine.Circulation 10/2001; 104(10):1165-70. · 15.20 Impact Factor
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ABSTRACT: Renal oxygen tension is substantially lower in the medulla than in the cortex and is reduced in hypertensive rats, a model of oxidative stress. Expression of NADPH oxidase, the primary source for superoxide anion (O(2)(-)*) in the kidney, is elevated in hypertension. Because molecular oxygen (O(2)) is required for O(2)(-)* formation, we tested the hypothesis that renal NADPH oxidase activity is limited by low O(2). O(2)(-)* production by rat kidney tissue or cultured cells exposed to levels of Po(2) that mimics those in the kidney was assessed by lucigenin-enhanced chemiluminescence. NADPH-dependent O(2)(-)* production by kidney homogenates decreased reversibly by 60-90% after graded reductions of ambient O(2) from 10 to 0% (76 to 2 mmHg Po(2)). The NADPH-dependent O(2)(-)* production by the kidney homogenate was reduced by decreasing Po(2) below approximately 30 mmHg. The response of tissue homogenates to low Po(2) was not different between normotensive and hypertensive rats. Similarly, NADPH-dependent O(2)(-)* production was lower during 2% O(2) compared with 10% O(2) in rat proximal tubule cells (-57 +/- 1%), vascular smooth muscle (-42 +/- 5%), cardiomyocytes (-57 +/- 1%), and mouse inner medulla collecting duct cells (-58 +/- 3%). We conclude that O(2)(-)* production by NADPH oxidase is dependent on availability of O(2). Therefore, O(2)(-)* generation may be limited in the kidney, both in the normal renal medulla and in the cortex of hypertensive kidneys.American journal of physiology. Renal physiology 11/2005; 289(4):F749-53. · 3.61 Impact Factor
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ABSTRACT: Blood vessels express 3 isoforms of superoxide dismutase (SOD): cytosolic or copper-zinc SOD (CuZn-SOD), manganese SOD (Mn-SOD) localized in mitochondria, and an extracellular form of CuZn-SOD (EC-SOD). Because there are no selective pharmacological inhibitors of individual SOD isoforms, the functional importance of the different SODs has been difficult to define. Recent molecular approaches, primarily the use of genetically-altered mice and viral-mediated gene transfer, have allowed investigators to begin to define the role of specific SOD isoforms in vascular biology. This review will focus mainly on the role of individual SODs in relation to endothelium under normal conditions and in disease states. This area is important because reactive oxygen species and superoxide anion are thought to play major roles in changes in vascular structure and function in pathophysiology.Arteriosclerosis Thrombosis and Vascular Biology 09/2004; 24(8):1367-73. · 6.34 Impact Factor