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Kelsen S.,Center for Excellence in Cardiovascular Renal Research | He X.,Center for Excellence in Cardiovascular Renal Research | Chade A.R.,Center for Excellence in Cardiovascular Renal Research | Chade A.R.,University of Mississippi Medical Center
American Journal of Physiology - Renal Physiology | Year: 2012

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution regarding antioxidant strategies in RAS. © 2012 the American Physiological Society.

Zouein F.A.,University of Mississippi Medical Center | Zouein F.A.,Center for Excellence in Cardiovascular Renal Research | Duhe R.J.,University of Mississippi Medical Center | Booz G.W.,University of Mississippi Medical Center | Booz G.W.,Center for Excellence in Cardiovascular Renal Research
Growth Factors | Year: 2011

The four Janus kinases (JAKs) comprise a family of intracellular, nonreceptor tyrosine kinases that first gained attention as signaling mediators of the type I and type II cytokine receptors. Subsequently, the JAKs were found to be involved in signaling downstream of the insulin receptor, a number of receptor tyrosine kinases, and certain G-protein coupled receptors. Although a number of cytoplasmic targets for the JAKs have been identified, their predominant action was found to be the phosphorylation and activation of the signal transducers and activators of transcription (STAT) factors. Through the STATs, the JAKs activate gene expression linked to cellular stress, proliferation, and differentiation. The JAKs are especially important in hematopoiesis, inflammation, and immunity, and aberrant JAK activity has been implicated in a number of disorders including rheumatoid arthritis, psoriasis, polycythemia vera, and myeloproliferative diseases. Although once thought to reside strictly in the cytoplasm, recent evidence shows that JAK1 and JAK2 are present in the nucleus of certain cells often under conditions associated with high rates of cell growth. Nuclear JAKs have now been shown to affect gene expression by activating other transcription factors besides the STATs and exerting epigenetic actions, for example, by phosphorylating histone H3. The latter action derepresses global gene expression and has been implicated in leukemogenesis. Nuclear JAKs may have a role as well in stem cell biology. Here we describe recent developments in understanding the noncanonical nuclear actions of JAK1 and JAK2. © 2011 Informa UK, Ltd.

Wallace K.,Center for Excellence in Cardiovascular Renal Research | Cornelius D.C.,University of Mississippi Medical Center | Scott J.,University of Mississippi Medical Center | Heath J.,Center for Excellence in Cardiovascular Renal Research | And 3 more authors.
Hypertension | Year: 2014

Preeclampsia is associated with oxidative stress, which is suspected to play a role in hypertension, placental ischemia, and fetal demise associated with the disease. Various cellular sources of oxidative stress, such as neutrophils, monocytes, and CD4+ T cells have been suggested as culprits in the pathophysiology of preeclampsia. The objective of this study was to examine a role of circulating and placental CD4+ T cells in oxidative stress in response to placental ischemia during pregnancy. CD4+ T cells and oxidative stress were measured in preeclamptic and normal pregnant women, placental ischemic and normal pregnant rats, and normal pregnant recipient rats of placental ischemic CD4+ T cells. Women with preeclampsia had significantly increased circulating (P=0.02) and placental CD4+ T cells (P=0.0001); lymphocyte secretion of myeloperoxidase (P=0.004); and placental reactive oxygen species (P=0.0004) when compared with normal pregnant women. CD4+ T cells from placental ischemic rats cause many facets of preeclampsia when injected into normal pregnant recipient rats on gestational day 13. On gestational day 19, blood pressure increased in normal pregnant recipients of placental ischemic CD4+ T cells (P=0.002) compared with that in normal pregnant rats. Similar to preeclamptic patients, CD4+ T cells from placental ischemic rats secreted significantly more myeloperoxidase (P=0.003) and induced oxidative stress in cultured vascular cells (P=0.003) than normal pregnant rat CD4+Tcells. Apocynin, a nicotinamide adenine dinucleotide phosphate inhibitor, attenuated hypertension and all oxidative stress markers in placental ischemic and normal pregnant recipient rats of placental ischemic CD4+Tcells (P=0.05). These data demonstrate an important role for CD4+ T cells in mediating another factor, oxidative stress, to cause hypertension during preeclampsia. © 2014 American Heart Association, Inc.

Speed J.S.,University of Mississippi Medical Center | Speed J.S.,Center for Excellence in Cardiovascular Renal Research | Lamarca B.,University of Mississippi Medical Center | Lamarca B.,Center for Excellence in Cardiovascular Renal Research | And 7 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011

Although it is well established that the renal endothelin (ET-1) system plays an important role in regulating sodium excretion and blood pressure through activation of renal medullary ETB receptors, the role of this system in Dahl salt-sensitive (DS) hypertension is unclear. The purpose of this study was to determine whether the DS rat has abnormalities in the renal medullary endothelin system when maintained on a high sodium intake. The data indicate that Dahl saltresistantrats (DR) on a high-salt diet had a six-fold higher urinary endothelin excretion than in the DR rats with low Na+ intake (17.8 ± 4 pg/day vs. 112 ± 44 pg/day). In sharp contrast, urinary endothelin levels increased only twofold in DS rats in response to a high Na+ intake (13 ± 2 pg/day vs. 29.8 ± 5.5 pg/day). Medullary endothelin concentration in DS rats on a high-Na+ diet was also significantly lower than DR rats on a high-Na+ diet (312.8 pg/mg vs. 70.9 ± 5 pg/mg). Furthermore, DS rats had a significant reduction in medullary ETB receptor expression compared with DR rats while on a high-Na+ diet. Finally, chronic infusion of ET-1 directly into the renal medulla blunted Dahl salt-sensitive hypertension. These data indicate that a decrease in medullary production of ET-1 in the DS rat could play an important role in the development of salt-sensitive hypertension observed in the DS rat. © 2011 the American Physiological Society.

Tam Tam K.B.,University of Mississippi Medical Center | Lamarca B.,University of Mississippi Medical Center | Lamarca B.,Center for Excellence in Cardiovascular Renal Research | Arany M.,Center for Excellence in Cardiovascular Renal Research | And 5 more authors.
American Journal of Hypertension | Year: 2011

Background Preeclampsia is associated with increased levels of reactive oxygen species (ROS) and the antiangiogenic factor, soluble fms-like tyrosine kinase-1 (sFlt-1). Moreover, recent studies have indicated that chronic sFlt-1 excess causes hypertension in pregnant animals. The purpose of this study was to evaluate the role of ROS in mediating sFlt-1-induced hypertension in the pregnant rat. Methods Mean arterial pressure (MAP), and plasma sFlt-1 and tissue ROS levels were measured in the following groups: (i) pregnant controls; (ii) sFlt-1-treated pregnant rats; (iii) Tempol-treated pregnant rats; (iv) sFlt-1- and Tempol-treated pregnant rats. Results MAP increased from 104 2mmHg in pregnant control rats to 118 3mmHg (P =0.002) in sFlt-1-infused rats. Basal and nicotinamide adenine dinucleotide phosphate (NADPH)-stimulated levels of tissue ROS were increased in response to excess sFlt-1 during pregnancy. Pretreatment with Tempol attenuated oxidative stress and hypertension in response to sFlt-1. Conclusions ROS play an important role in mediating hypertension in response to chronic sFlt-1 excess during pregnancy. © 2011 American Journal of Hypertension, Ltd.

PubMed | Center for Excellence in Cardiovascular Renal Research
Type: Journal Article | Journal: American journal of physiology. Regulatory, integrative and comparative physiology | Year: 2012

Preeclampsia is associated with autoimmune cells T(H)17, secreting interleukin-17, autoantibodies activating the angiotensin II type I receptor (AT1-AA), and placental oxidative stress (ROS). The objective of our study was to determine whether chronic IL-17 increases blood pressure by stimulating ROS and AT1-AAs during pregnancy. To answer this question four groups of rats were examined: normal pregnant (NP, n = 20), NP+IL-17 (n = 12), NP+tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) (n = 7) (a superoxide dismutase mimetic that scavenges ROS), and NP+IL-17+tempol (n = 11). IL-17 (150 pg/day) was infused into NP rats while tempol was administered via the drinking water ad libitum. On day 19 blood pressure (MAP) was recorded, and plasma, urine, and tissue were collected for isolation of ROS detected by chemilluminescent technique. Urinary isoprostane was measured by ELISA. AT1-AAs were determined via cardiomyocyte assay and expressed as beats per minute. MAP increased from 98 3 mmHg in NP to 123 3 mmHg in IL-17-infused NP rats. Urinary isoprostane increased from 1,029 1 in NP to 3,526 2 pgmg(-1)day(-1) in IL-17-infused rats (P < 0.05). Placental ROS was 436 4 RLUml(-1)min(-1) (n = 4) in NP and 702 5 (n = 5) RLUml(-1)min(-1) in IL-17-treated rats. Importantly, AT1-AA increased from 0.41 0.05 beats/min in NP rats (n = 8) to 18.4 1 beats/min in IL-17 rats (n = 12). Administration of tempol attenuated the hypertension (101 3 mmHg) ROS (459 5 RLUml(-1)min(-1)) and blunted AT1-AAs (7.3 0.6 beats/min) in NP+IL-17+tempol-treated rats. Additionally, AT1 receptor blockade inhibited IL-17-induced hypertension and placental oxidative stress. MAP was 105 5 mmHg and ROS was 418 5 RLUml(-1)min(-1) in NP+IL 17-treated with losartan. These data indicate that IL-17 causes placental oxidative stress, which serves as stimulus modulating AT1-AAs that may play an important role in mediating IL-17-induced hypertension during pregnancy.

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