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      Oxidative Stress and Renal Dysfunction in Salt-Sensitive Hypertension

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          Hypertension is a risk factor for the development of end-stage renal disease. The mechanisms underlying hypertensive nephropathy are poorly understood. There is evidence, however, that in hypertension there is an accumulation of partially reduced oxygen and its derivatives, known collectively as reactive oxygen species, which may contribute to progressive renal dysfunction. In the present study, we assess the contribution of oxidative stress in the development of salt-dependent hypertensive nephrosclerosis. Going beyond previous end point studies, which inferred renal function either indirectly or only qualitatively, we have determined oxidative stress concurrently with direct and quantitative measurements of renal function (via inulin and p-aminohippuric acid clearances). Moreover, in this time-dependent study, the measurements have been taken under low- as well as high-salt diets. As was expected from previous studies, in the Dahl salt-sensitive rat, a high-salt diet (8% NaCl) resulted in the development of hypertension, in a decreased glomerular filtration rate, and in a decreased renal plasma flow as compared with the normotensive control, the Dahl salt-resistant rat. In addition, however, we found clear evidence for the accumulation of reactive oxygen species in renal tissue homogenates of Dahl salt-sensitive rats on the high-salt diet. Our time-dependent protocol also indicated that renal oxidative stress follows, in time, the development of hypertension. We also found that after 2 weeks of increased salt loading, Dahl salt-sensitive rats excreted less cyclic guanosine monophosphate and NO<sub>x</sub> than Dahl salt-resistant rats on the same diet. It is known that urinary cyclic guanosine monophosphate and NO<sub>x</sub> represent the activity and stable derivatives of renal NO·, respectively, and that they closely correlate with renal vascular resistance. Therefore, our results suggest that, in the Dahl salt-sensitive rat, increased oxidative stress is associated with salt-dependent hypertensive nephrosclerosis and that decreased NO· bioavailability may represent a common factor responsible for the vascular and glomerular dysfunction.

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          The increasing importance of nitric oxide synthase has been underscored by the elucidation of its role in a growing number of normal and pathophysiological processes. Therefore, techniques for detection of nitrite/nitrate, oxidation products of the enzymatic conversion of arginine to citrulline and nitric oxide, should serve as useful tools in defining the contribution of NO synthase to these processes. We have developed a rapid and sensitive fluorometric assay for quantification of nitrite/nitrate based upon the reaction of nitrite with 2,3-diaminonaphthalene to form the fluorescent product, 1-(H)-naphthotriazole. The assay can be used to detect 10 nM nitrite, making it 50-100 times more sensitive than the well-known Griess assay. Moreover, the assay is adaptable to a 96-well plate format, facilitating the handling of a large number of samples including conditioned media from cell culture or the nitrite generated by the purified enzyme. Nitrite/nitrate levels in blood can also be monitored using this assay when it is combined with a filtration step (to remove hemoglobin) followed by conversion of the nitrate to nitrite by nitrate reductase. Thus, this fluorometric method combines speed and sensitivity with the handling of a large number of samples for the quantification of nitrite generated from in vivo and in vitro sources.
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            Lucigenin luminescence as a measure of intracellular superoxide dismutase activity in Escherichia coli.

            Lucigenin and paraquat are similar in that each can be taken into Escherichia coli and can then mediate O2.- production by cycles of univalent reduction, to the corresponding monocation radical, followed by autoxidation. Thus, both compounds caused induction of enzymes that are regulated by the soxRS regulon. The lucigenin cation radical has the added property of reacting with O2.-, in a radical-radical addition, to yield an unstable dioxetane, whose decomposition yields light. Superoxide dismutases (SOD), by decreasing [O2.-], inhibit light production and to the same degree inhibit other O2.(-)-dependent reactions in the cell. Lucigenin luminescence was used to show that the levels of SOD in the parental strain provide approximately 95% protection of all O2.(-)-sensitive targets in E. coli. This degree of protection was so close to the limit of 100% that halving the parental level of [SOD], or increasing it 5-fold, had only marginal effects on the intensity of lucigenin-dependent luminescence.
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              Projections of hypertension-related renal disease in middle-aged residents of the United States.

              To establish nationwide projections for hypertension-related renal disease among middle-aged residents of the United States and compare disease burden in demographic subgroups. Integrated analysis of data from the US Census, the National Health and Nutrition Examination Survey of 1976 through 1980 (NHANES II), the 1971 through 1975 NHANES I Epidemiologic Follow-up Study, the Hypertension Detection and Follow-up Program trial, and the US Renal Data System. African-American and white residents of the United States, aged 30 to 69 years. Incidence rates and counts of hypertension, hypertension-related hypercreatinemia, and hypertension-related end-stage renal disease (ESRD). Each year, approximately 1.8 million middle-aged Americans develop hypertension, 140,000 develop hypertension-related hypercreatinemia, and 5300 develop hypertension-related ESRD. African Americans are at increased risk for hypertension (relative risk [RR], 1.6; population-attributable risk [PAR], 5%), hypercreatinemia if hypertensive (RR, 2.4; PAR, 18%), ESRD if hypertensive with hypercreatinemia (RR, 2.7; PAR, 32%), and hypertension-related ESRD overall (RR, 8.0; PAR, 44%). Compared with women, men are at increased risk for hypertension (RR, 1.3; PAR, 13%) and hypertension-related ESRD (RR, 1.6; PAR, 23%). Most cases of hypercreatinemia in hypertensives (73%) occur among those with mild hypertension. Progression to ESRD is rare in persons with hypertension-related renal disease, and factors other than blood pressure probably play an important role. A large proportion of hypertension-related renal disease cases occur among population subgroups considered to be at low risk. Interventions that favorably influence factors associated with the progression of hypertension-related renal disease in African Americans, in men, and in persons with mild hypertension, hold the greatest potential for reducing the population burden of hypertension-related ESRD.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                29 June 2001
                : 24
                : 2
                : 116-123
                Whitaker Cardiovascular Institute, Evans Department of Medicine, Boston University School of Medicine, Boston, Mass., USA
                54217 Kidney Blood Press Res 2001;24:116–123
                © 2001 S. Karger AG, Basel

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                Figures: 3, Tables: 2, References: 52, Pages: 8
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