Tempol Attenuates the Development of Hypertensive Renal Injury in Dahl Salt-Sensitive Rats

Hisaki, Ryohei; Fujita, Hirotaka; Saito, Fumio; Kushiro, Toshio

doi:10.1016/j.amjhyper.2004.11.045

Cited by 46 publications

(43 citation statements)

References 30 publications

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“…These studies, together with our present data, implicate T lymphocytes in the elevation of the oxidative state during hypertensive conditions. Treatment with the antioxidant tempol has been proven to decrease hypertension and renal damage in Dahl SS rats (18,26). In the present set of experiments, tempol treatment during the high-salt period ameliorated hypertension and albuminuria without affecting the infiltration of T cells into the kidney, which remained elevated.…”

Section: Discussionmentioning

confidence: 48%

Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease

Miguel

Guo

Lund

et al. 2011

American Journal of Physiology-Renal Physiology

140

136

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The present studies examined the role and mechanism of action of infiltrating T lymphocytes in the kidney during salt-sensitive hypertension. Infiltrating T lymphocytes in the Dahl salt-sensitive (SS) kidney significantly increased from 7.2 Ϯ 1.8 ϫ 10 5 cells/2 kidneys to 18.2 Ϯ 3.9 ϫ 10 5 cells/2 kidneys (n ϭ 6/group) when dietary NaCl was increased from 0.4 to 4.0%. Furthermore, the expression of immunoreactive p67 phox , gp91 phox , and p47 phox subunits of NADPH oxidase was increased in T cells isolated from the kidneys of rats fed 4.0% NaCl. The urinary excretion of thiobarbituric acid-reactive substances (TBARS; an index of oxidative stress) also increased from 367 Ϯ 49 to 688 Ϯ 92 nmol/day (n ϭ 8/group) when NaCl intake was increased in Dahl SS rats. Studies were then performed on rats treated with a daily injection of vehicle (5% dextrose) or tacrolimus (0.25 mg · kg Ϫ1 · day Ϫ1 ip), a calcineurin inhibitor that suppresses immune function, during the period of high-NaCl intake (n ϭ 5/group). In contrast to the immune cell infiltration, increased NADPH oxidase expression, and elevated urine TBARS excretion in vehicle-treated Dahl SS fed high salt, these parameters were unaltered as NaCl intake was increased in Dahl SS rats administered tacrolimus. Moreover, tacrolimus treatment blunted high-salt mean arterial blood pressure and albumin excretion rate (152 Ϯ 3 mmHg and 20 Ϯ 9 mg/day, respectively) compared with values in dextrose-treated Dahl SS rats (171 Ϯ 8 mmHg and 74 Ϯ 28 mg/day). These experiments indicate that blockade of infiltrating immune cells is associated with decreased oxidative stress, an attenuation of hypertension, and a reduction of renal damage in Dahl SS rats fed high salt. reactive oxygen species generation; chronic renal insufficiency OXIDATIVE STRESS, DEFINED as a persistent imbalance between the production of highly reactive molecular species (mainly oxygen and nitrogen) and antioxidant defenses, has been implicated in pathophysiological conditions that affect the cardiovascular system (12,28,35). Increased levels of oxidative stress have been described in experimental models of hypertension (2, 6, 20) and hypertensive patients (22,35).A number of studies in animal models of hypertension demonstrated elevations of blood pressure by stimulation of reactive oxygen species (ROS) generation (24,44,47). Moreover, treatment with a variety of antioxidants reduces blood pressure in several genetic and experimental models of hypertension (4,7,30,40,48). One of the most important biological mechanisms for the production of ROS results from the generation of superoxide (O 2 ·Ϫ ) from O 2 by the enzyme NADPH oxidase (14). Stimulation of NADPH oxidase appears to be the primary source of oxidants in systemic arterial vessels in renovascular hypertension (16), ANG II-induced hypertension (8, 34), DOCA-salt hypertension (42, 49), chronic renal insufficiency (47), and the spontaneously hypertensive rat (49). In humans, NADPH oxidase is the principal source of O 2 ·Ϫ in vascular smooth muscle cells (1...

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Section: Discussionmentioning

confidence: 48%

Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease

Miguel

Guo

Lund

et al. 2011

American Journal of Physiology-Renal Physiology

140

136

View full text Add to dashboard Cite

show abstract

“…Tsukahara et al (2003) reported that high degree of oxidative stress in the renal tissue coincides with biochemical signs typical of DN, such as high levels of UAE and urinary proteins. Moreover, Hisaki et al (2005) demonstrated that a high salt intake increased urinary 8-OHdG excretion in a rat model of hypertension. Based on our results, urinary 8-OHdG excretion was significantly higher in WFR with high-salt dietinduced hypertension than in WFR fed a with normal-salt diet.…”

Section: Discussionmentioning

confidence: 97%

Hypertension aggravates glomerular dysfunction with oxidative stress in a rat model of diabetic nephropathy

Tomohiro¹,

Kumai

Sato³

et al. 2007

Life Sciences

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“…The antioxidant ␣-tocopherol prevents the development of hypertension and renal dysfunction in SS rats (7,28,96). The superoxide dismutase mimetic tempol reduces glomerular injury (43,63) and MAPK activity in Dahl SS rats (76). DHA attenuates the development of hypertension by decreasing NADPH oxidase activity in rats infused with ANG II (20).…”

Section: Discussionmentioning

confidence: 99%

Signaling pathways modulated by fish oil in salt-sensitive hypertension

Díaz-Encarnación¹,

Warner²,

Gray³

et al. 2008

American Journal of Physiology-Renal Physiology

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Diaz Encarnacion MM, Warner GM, Gray CE, Cheng J, Keryakos HK, Nath KA, Grande JP. Signaling pathways modulated by fish oil in salt-sensitive hypertension. Am J Physiol Renal Physiol 294: F1323-F1335, 2008. First published April 2, 2008 doi:10.1152/ajprenal.00401.2007.-Although many studies have indicated that fish oil (FO) improves cardiovascular risk factors and reduces histopathological manifestations of injury in experimental renal injury models, potential mechanisms underlying this protective effect have not been adequately defined. The objective of this study was to identify potential signaling pathways that confer protection in the Dahl rat model of salt-sensitive hypertension. Male Dahl saltsensitive rats (n ϭ 10/group) were provided with formulated diets containing 8% NaCl, 20% protein, and 25% FO or 25% corn oil (CO) for 28 days. FO reduced blood pressure (Ϫ11% at 4 wk; P Ͻ 0.05), urine protein excretion (Ϫ45% at 4 wk; P Ͻ 0.05), plasma cholesterol and triglyceride levels (Ϫ54%, P Ͻ 0.001; and Ϫ58%, P Ͻ 0.05), and histopathological manifestations of renal injury, including vascular hypertrophy, segmental and global glomerular sclerosis, interstitial fibrosis, and tubular atrophy. Interstitial inflammation was significantly reduced by FO (Ϫ32%; P Ͻ 0.001), as assessed by quantitative analysis of ED1-positive cells in sections of the renal cortex. FO reduced tubulointerstitial proliferative activity, as assessed by Western blot analysis of cortical homogenates for PCNA (Ϫ51%; P Ͻ 0.01) and quantitative analysis of Mib-1-stained sections of the renal cortex (Ϫ42%; P Ͻ 0.001). Decreased proliferative activity was associated with reduced phospho-ERK expression (Ϫ37%; P Ͻ 0.005) and NF-B activation (Ϫ42%; P Ͻ 0.05). FO reduced cyclooxygenase (COX)-2 expression (Ϫ63%; P Ͻ 0.01) and membrane translocation of the NADPH oxidase subunits p47 phox and p67 phox (Ϫ26 and Ϫ34%; P Ͻ 0.05). We propose that FO ameliorates renal injury in Dahl salt-sensitive rats through the inhibition of ERK, decreased NF-B activation, inhibition of COX-2 expression, and decreased NADPH oxidase activation.fibrosis; glomerulosclerosis; docosahexaenoic acid; eicosapentaenoic acid; rat HYPERTENSIVE NEPHROSCLEROSIS is the second most common cause of end-stage renal disease in the United States (98). Over 70% of the 5.6 million individuals in the United States with elevated serum creatinine levels are hypertensive (16). The risk of end-stage renal disease is directly related to the degree of blood pressure elevation. Hypertension, which occurs in as many as 43 million individuals, is clearly a multifactorial disorder resulting from a variety of environmental and genetic factors. Of the environmental factors, excess dietary salt intake appears to be one of the most important (93, 103). Of note, salt sensitivity is an independent cardiovascular risk factor in patients with hypertension (69).Given the prevalence of hypertension, nontoxic, easily tolerated therapeutic agents that complement standard antihypertensive therapy may play a critical ...

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Tempol Attenuates the Development of Hypertensive Renal Injury in Dahl Salt-Sensitive Rats

Cited by 46 publications

References 30 publications

Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease

Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease

Hypertension aggravates glomerular dysfunction with oxidative stress in a rat model of diabetic nephropathy

Signaling pathways modulated by fish oil in salt-sensitive hypertension

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