This study examined mechanisms by which immune cells participate in the development of hypertension and renal disease in Dahl salt-sensitive (SS) rats. Increasing dietary salt from 0.4% to 4.0% NaCl significantly increased renal infiltration of T lymphocytes from 8.8 +/- 1.2 x 10(5) to 14.4 +/- 2.0 x 10(5) cells/2 kidneys, increased arterial blood pressure from 131 +/- 2 to 165 +/- 6 mmHg, increased albumin excretion rate from 17 +/- 3 to 129 +/- 20 mg/day, and resulted in renal glomerular and tubular damage. Furthermore, renal tissue ANG II was not suppressed in the kidneys of SS rats fed 4.0% NaCl. Administration of the immunosuppressive agent mycophenolate mofetil (MMF; 20 mg.kg(-1).day(-1)) prevented the infiltration of T lymphocytes and attenuated Dahl SS hypertension and renal disease. In contrast to vehicle-treated rats, Dahl SS rats administered MMF demonstrated a suppression of renal tissue ANG II from 163 +/- 26 to 88 +/- 9 pg/g of tissue when fed high salt. Finally, it was demonstrated that the T lymphocytes isolated from the kidney possess renin and angiotensin-converting enzyme activity. These data indicate that infiltrating T cells are capable of participating in the production of ANG II and are associated with increased intrarenal ANG II, hypertension, and renal disease. The suppression of T-cell infiltration decreased intrarenal ANG II and prevented Dahl SS hypertension and kidney damage. As such, infiltrating cells are capable of participating in the established phase of Dahl SS hypertension.

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...

Research studying the role of inflammation in hypertension and cardiovascular disease has flourished in recent years; however, the exact mechanisms by which the activated immune cells lead to the development and maintenance of hypertension remain to be elucidated. The objective of this brief review is to summarize and discuss the most recent findings in the field, with special emphasis on potential therapeutics to treat or prevent hypertension. This review will cover novel immune cell subtypes recently associated to the disease including the novel role of cytokines, toll-like receptors and inflammasomes in hypertension.

Besides differential methylation, DNA methylation variation has recently been proposed and demonstrated to be a potential contributing factor to cancer risk. Here we aim to examine whether differential variability in methylation is also an important feature of obesity, a typical non-malignant common complex disease. We analyzed genome-wide methylation profiles of over 470,000 CpGs in peripheral blood samples from 48 obese and 48 lean African-American youth aged 14–20 y old. A substantial number of differentially variable CpG sites (DVCs), using statistics based on variances, as well as a substantial number of differentially methylated CpG sites (DMCs), using statistics based on means, were identified. Similar to the findings in cancers, DVCs generally exhibited an outlier structure and were more variable in cases than in controls. By randomly splitting the current sample into a discovery and validation set, we observed that both the DVCs and DMCs identified from the first set could independently predict obesity status in the second set. Furthermore, both the genes harboring DMCs and the genes harboring DVCs showed significant enrichment of genes identified by genome-wide association studies on obesity and related diseases, such as hypertension, dyslipidemia, type 2 diabetes and certain types of cancers, supporting their roles in the etiology and pathogenesis of obesity. We generalized the recent finding on methylation variability in cancer research to obesity and demonstrated that differential variability is also an important feature of obesity-related methylation changes. Future studies on the epigenetics of obesity will benefit from both statistics based on means and statistics based on variances.

Abstract-The present study evaluated the influence and mechanism of action of dietary protein intake in Dahl SS hypertension and renal disease. Rats were fed isocaloric diets with low (6%), normal (18%), or high (30%) amounts of protein and 0.4% NaCl from 5 to 12 weeks of age; the NaCl content of the diets was then increased to 4.0% NaCl from 12 to 15 weeks of age. Rats fed the high-protein diet developed the highest mean arterial blood pressure and urine albumin-to-creatinine ratio when fed the 4.0% NaCl diet (153Ϯ7 mm Hg and 8.0Ϯ2.4, respectively) compared to rats fed normal protein (132Ϯ3 mm Hg, 1.2Ϯ0.3) or low-protein (132Ϯ6 mm Hg, 0.3Ϯ0.1) diets. Significantly greater numbers of infiltrating T lymphocytes were observed in kidneys of SS rats fed the high-protein diet (18.9Ϯ3ϫ10 5 cells) than in rats fed the low-protein diet (9.1Ϯ3ϫ10 5 cells). Furthermore, treatment of SS rats fed the high-protein diet with the immunosuppressant agent mycophenolate mofetil (20 mg/kg per day, ip) significantly reduced the number of infiltrating T cells in the kidneys (from 18.9Ϯ2.7 to 10.6Ϯ2.0ϫ10 5 cells) while decreasing blood pressure (from 133Ϯ3 to 113Ϯ4 mm Hg) and the albumin/creatinine ratio (from 10.9Ϯ2.3 to 5.4Ϯ1.2). These results demonstrate that restriction of protein intake protects the Dahl SS rats from hypertension and kidney disease and indicates that infiltrating immune cells play a pathological role in Dahl SS rats fed a high-protein diet. Moreover, the results show that hypertension in Dahl SS rats is sensitive to both NaCl and protein intake. (Hypertension. 2011;57:269-274.)

The present studies evaluated intrarenal hemodynamics, pressure natriuresis, and arterial blood pressure in rats following recovery from renal ischemia-reperfusion (I/R) injury. Acute I/R injury, induced by 40 min of bilateral renal arterial occlusion, resulted in an increase in plasma creatinine that resolved within a week. Following 5 wk of recovery on a 0.4% NaCl diet, the pressure-natriuresis response was assessed in anesthetized rats in which the kidney was denervated and extrarenal hormones were administered intravenously. Increasing renal perfusion pressure (RPP) from 107 to 141 mmHg resulted in a fourfold increase in urine flow and sodium excretion in sham control rats. In comparison, pressure diuresis and natriuresis were significantly attenuated in post-I/R rats. In sham rats, glomerular filtration rate (GFR) averaged 1.6 +/- 0.2 mlxmin(-1)xg kidney weight(-1) and renal blood flow (RBF) averaged 7.8 +/- 0.7 mlxmin(-1)xg kidney weight(-1) at RPP of 129 mmHg. Renal cortical blood flow, measured by laser-Doppler flowmetry, was well autoregulated whereas medullary blood flow and renal interstitial hydrostatic pressure increased directly with elevated RPP in sham rats. In contrast, GFR and RBF were significantly reduced whereas medullary perfusion and interstitial pressure demonstrated an attenuated response to RPP in post-I/R rats. Further experiments demonstrated that conscious I/R rats develop hypertension when sodium intake is increased. The present data indicate that the pressure-natriuretic-diuretic response in I/R rats is blunted because of a decrease in GFR and RBF and the depressed pressure-dependent increase in medullary blood flow and interstitial pressure.

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ET) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ET and ET receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ET receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ET receptor antagonism may provide a strategy for the prevention of renal complications of SCD.

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