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The Epstein–Barr virus (EBV) has a very high prevalence (>90% in adults), establishes a lifelong latency after primary infection, and exerts an oncogenic potential. This dsDNA virus encodes for various molecules, including microRNAs (miRs), which can be detected in the latent and lytic phases with different expression levels and affect, among others, immune evasion and malignant transformation. In this study, the different EBV miRs are quantified in EBV-positive lymphomas, and the impact on the host cell transcriptome of the most abundant EBV miRs will be analyzed using comparative RNA sequencing analyses. The EBV miRs ebv-miR-BART1, -BART4, -BART17, and -BHRF1-1 were most highly expressed, and their selective overexpression in EBV-negative human cells resulted in a large number of statistically significantly down- and up-regulated host cell genes. Functional analyses showed that these dysregulated target genes are involved in important cellular processes, including growth factor pathways such as WNT, EGF, FGF, and PDGF, as well as cellular processes such as apoptosis regulation and inflammation. Individual differences were observed between these four analyzed EBV miRs. In particular, ebv-miR-BHRF1-1 appears to be more important for malignant transformation and immune evasion than the other EBV miRs. [ABSTRACT FROM AUTHOR]

Stretch-induced vascular tone is an important element of autoregulatory adaptation of cerebral vasculature to maintain cerebral flow constant despite changes in perfusion pressure. Little is known as to the regulation of tone in senescent basilar arteries. We tested the hypothesis, that thin filament mechanisms in addition to smooth muscle myosin-II regulatory-light-chain- (MLC20)-phosphorylation and non-muscle-myosin-II, contribute to regulation of stretch-induced tone. In young BAs (y-BAs) mechanical stretch does not lead to spontaneous tone generation. Stretch-induced tone in y-BAs appeared only after inhibition of NO-release by L-NAME and was fully prevented by treatment with 3 µmol/L RhoA-kinase (ROK) inhibitor Y27632. L-NAME-induced tone was reduced in y-BAs from heterozygous mice carrying a point mutation of the targeting-subunit of the myosin phosphatase, MYPT1 at threonine696 (MYPT1-T696A/+). In y-BAs, MYPT1-T696A-mutation also blunted the ability of L-NAME to increase MLC20-phosphorylation. In contrast, senescent BAs (s-BAs; >24 months) developed stable spontaneous stretch-induced tone and pharmacological inhibition of NO-release by L-NAME led to an additive effect. In s-BAs the MYPT1-T696A mutation also blunted MLC20-phosphorylation, but did not prevent development of stretch-induced tone. In s-BAs from both lines, Y27632 completely abolished stretch- and L-NAME-induced tone. In s-BAs phosphorylation of non-muscle-myosin-S1943 and PAK1-T423, shown to be down-stream effectors of ROK was also reduced by Y27632 treatment. Stretch- and L-NAME tone were inhibited by inhibition of non-muscle myosin (NM-myosin) by blebbistatin. We also tested whether the substrate of PAK1 the thin-filament associated protein, caldesmon is involved in the regulation of stretch-induced tone in advanced age. BAs obtained from heterozygotes Cald1+/- mice generated stretch-induced tone already at an age of 20-21 months old BAs (o-BA). The magnitude of stretch-induced tone in Cald1+/- o-BAs was similar to that in s-BA. In addition, truncation of caldesmon myosin binding Exon2 (CaD-ΔEx2-/-) did not accelerate stretch-induced tone. Our study indicates that in senescent cerebral vessels, mechanisms distinct from MLC20 phosphorylation contribute to regulation of tone in the absence of a contractile agonist. While in y-and o-BA the canonical pathways, i.e., inhibition of MLCP by ROK and increase in pMLC20, predominate, tone regulation in senescence involves ROK regulated mechanisms, involving non-muscle-myosin and thin filament linked mechanisms involving caldesmon. [ABSTRACT FROM AUTHOR]

Upper urinary tract peristalsis is generated in the proximal renal pelvis that connects to the renal parenchyma at the pelvis-kidney junction. It may be exposed to the high renal endothelin-1 (ET-1) concentrations. Dietary NaCl restriction increases renal pelvic [ET.sub.A] receptor expression. We investigated the contribution of [ET.sub.A] and [ET.sub.B] receptors to ET-1-stimulated rat renal pelvic contractions and whether the sensitivity of renal pelvic contractile activity to ET-1 stimulation increases with dietary NaCl restriction. We tested whether ET-1-induced contractile activity depends on cyclooxygenase (COX)-1 or -2 and to what extent spontaneous as well as agonist-induced peristalsis depends on Rho kinases (ROCK). Contractions of isolated renal pelvises were investigated by myography. ET-1 concentration-dependently increased pelvic contractile activity up to 400% of basal activity. ETA but not [ET.sub.B] receptor blockade inhibited ET-1-induced pelvic contractions. Basal and ET-1-stimulated contractions were similar in renal pelvises from rats on a high-NaCl diet or on a NaCl-deficient diet. COX-1 inhibition reduced spontaneous and almost completely blocked the ET-1-induced pelvic contractions. ROCK inhibition reduced spontaneous and ET-1 stimulated pelvic contractile activity by 90%. RT-PCR revealed that both ROCK isoenzymes are present in the renal pelvic wall. Western blot analyses did not show increased phosphorylation of ROCK substrates myosin phosphatase target subunit 1, ezrin, radixin, and moesin in ET-1-treated isolated renal pelvises. ET-1 is a powerful [ET.sub.A] receptor-dependent activator of renal pelvic contractions. COX-1 and ROCK activity are required for the ET-1 effects on pelvic contractions, which are not significantly affected by dietary NaCl intake. smooth muscle; urinary tract doi: 10.1152/ajpregu.00452.2010.

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which in turn decreases ERSNA via activation of the renorenal reflexes in the overall goal of maintaining low ERSNA. We now examined whether the ERSNA-induced increases in ARNA are modulated by dietary sodium and the role of endothelin (ET). The ARNA response to reflex increases in ERSNA was enhanced in high (HNa)- vs. low-sodium (LNa) diet rats, 7,560 [+ or -] 1,470 vs. 900 [+ or -] 390% * s. The norepinephrine (NE) concentration required to increase [PGE.sub.2] and substance P release from isolated renal pelvises was 10 pM in HNa and 6,250 pM in LNa diet rats. In HNa diet pelvises 10 pM NE increased [PGE.sub.2] release from 67 [+ or -] 6 to 150 [+ or -] 13 pg/min and substance P release from 6.7 [+ or -] 0.8 to 12.3 [+ or -] 1.8 pg/min. In LNa diet pelvises 6,250 pM NE increased [PGE.sub.2] release from 64 [+ or -] 5 to 129 [+ or -] 22 pg/min and substance P release from 4.5 [+ or -] 0.4 to 6.6 [+ or -] 0.7 pg/min. In the renal pelvic wall, ETB-R are present on unmyelinated Schwann cells close to the afferent nerves and ETA-R on smooth muscle cells. ETA-receptor (R) protein expression in the renal pelvic wall is increased in LNa diet. In HNa diet, renal pelvic administration of the ETB-R antagonist BQ788 reduced ERSNA-induced increases in ARNA and NE-induced release of [PGE.sub.2] and substance P. In LNa diet, the ETA-R antagonist BQ123 enhanced ERSNA-induced increases in ARNA and NE-induced release of substance P without altering [PGE.sub.2] release. In conclusion, activation of ETB-R and ETA-R contributes to the enhanced and suppressed interaction between ERSNA and ARNA in conditions of HNa and LNa diet, respectively, suggesting a role for ET in the renal control of ERSNA that is dependent on dietary sodium. sensory nerves; substance P; [PGE.sub.2]; endothelin A receptors; endothefin B receptors; renal pelvis; norepinephrine

Neonatal sympathectomy reduces arterial pressure in spontaneously hypertensive rats (SHR). In SHR transplanted with a kidney from sympathectomized SHR, arterial pressure was lower and less [Na.sup.+] sensitive than in SHR transplanted with a kidney from hydralazine-treated SHR. This study was performed to identify underlying renal mechanisms. Tests for differential renal mRNA expression of nine a priori selected genes revealed robust differences for renal medullary expression of the NADPH oxidase subunit [p47.sup.phox]. Therefore, we investigated the effects of neonatal sympathectomy on renal mRNA expression of NADPH oxidase subunits, NADPH oxidase activity, and renal function. In 10-wk-old sympathectomized SHR fed a 0.6% NaCl diet, medullary [p47.sup.phox] and [gp91.sup.phox] expression was 40% less than in hydralazine-treated SHR. Also, after a 1.8% NaCl diet, medullary [p47.sup.phox] mRNA expression was lower in sympathectomized than in hydralazine-treated SHR. We found lower cortical (-30%, P < 0.01) and medullary (-30%, P < 0.05) NADPH oxidase activities in sympathectomized than in hydralazine-treated or untreated SHR. Glomerular filtration rate, renal blood flow, medullary blood flow, and fractional [Na.sup.+] excretion in kidney grafts from sympathectomized and hydralazine-treated donors (n = 8 per group) were similar at baseline and in response to a 20-mmHg rise in renal perfusion pressure. Renal vascular resistance was lower in kidneys from sympathectomized than hydralazine-treated donors (25 [+ or -] 2 vs. 32 [+ or -] 4 mmHg x min x [ml.sup.-1], P < 0.05). The results indicate that the sympathetic nervous system contributes to the level of renal NADPH oxidase activity and to perinatal programming of alterations in renal vascular function that lead to elevated renal vascular resistance in SHR. inbred strains; kidney; sympathetic activity; gene expression doi:10.1152/ajpregu.00029.2006

The effects of neonatal sympathectomy of donors or recipients on post-transplantation arterial pressure were investigated in spontaneously hypertensive rats (SHR) by renal transplantation experiments. Conscious mean arterial pressure (MAP) and renal vascular resistance were 136 [+ or -] 1 mmHg and 15.5 [+ or -] 1.2 mmHg * [ml.sup.-1] * min * g in sympathectomized SHR (n = 8) vs. 158 [+ or -] 4 mmHg (P < 0.001) and 20.8 [+ or -] 1.1 mmHg * [ml.sup.-1] * min * g (P < 0.05) in controls (n = 10). Seven weeks after transplantation of a kidney from neonatally sympathectomized SHR donors, MAP in SHR recipients (n = 10) was 20 mmHg lower than in controls transplanted with a kidney from hydralazine-treated SHR (n = 10) (P < 0.05) associated with reduced sodium sensitivity of MAP. Neonatal sympathectomy also lowered MAP in F1-hybrids (F1H; SHR x Wistar-Kyoto rats). Within 6 wk after transplantation, renal grafts from untreated SHR increased MAP by 20 mmHg in sympathectomized F1H (n = 10) and by 35 mmHg in sham-treated F1H (n = 8) (P < 0.05). Neonatal sympathectomy induces chronic changes in SHR kidney function leading to a MAP reduction even when extrarenal sympathetic tone is restored. Generalized reduction in sympathetic tone resets the kidney-fluid system to reduced MAP and blunts the extent of arterial pressure rise induced by an SHR kidney graft. rats; inbred strains; kidney transplantation; sodium; catecholamines; guanethidine

The hypothesis was tested that low-frequency vasomotions in individual vascular beds are integrated by the cardiovascular system, such that new fluctuations at additional frequencies occur in arterial blood pressure. In anesthetized rats (n = 8), the sympathetic splanchnic and renal nerves were simultaneously stimulated at combinations of frequencies ranging from 0.075 to 0.8 Hz. Blood pressure was recorded together with mesenteric and renal blood flow velocities. Dual nerve stimulation at low frequencies ( rats; sympathetic nervous system; arterial blood pressure; blood pressure variability; Mayer waves

Grisk, Olaf, Bernd A. J. Frey, Andreas Uber, and Rainer Rettig. Sympathetic activity in early renal posttransplantation hypertension in rats. Am J Physiol Regulatory Integrative Comp Physiol 279: R1737-R1744, 2000.--The contribution of elevated sympathetic activity to the development of renal posttransplantation hypertension was investigated. F1 hybrids (FIH) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were transplanted with either an SHR or an FIH kidney and bilaterally nephrectomized. Three weeks after transplantation, sympathetic activity was assessed by measuring adrenal tyrosine hydroxylase (TH) mRNA content and recording splanchnic nerve activity (SNA) in conscious animals. To investigate the dependence of arterial pressure on sympathetic activity, animals were treated with the [[Alpha]sub.2]-adrenoceptor agonist guanabenz intracerebroventricularly. Mean arterial pressure (MAP) was 143 [+ or -] 4 mmHg in recipients of an SHR kidney (n = 15) versus 110 [+ or -] 3 mmHg in recipients of an F1H kidney (n = 10; P [is less than] 0.001). Adrenal TH mRNA content was 1.93 [+ or -] 0.15 fmol/[micro] g total RNA in recipients of an SHR kidney versus 1.96 [+ or -] 0.17 fmol/[micro] g total RNA in recipients of an F1H kidney (not significant). SNA did not differ significantly between recipients of an SHR kidney (n = 8) and recipients of an F1H kidney (n = 7) in terms of frequency and amplitude of synchronized nerve discharges. In response to cumulative intracerebroventricular administration of 10 and 20 [micro] g guanabenz, SNA fell to 51 [+ or -] 5% of control in recipients of an SHR kidney versus 44 [+ or -] 6% of control in recipients of an F1H kidney (not significant) accompanied by a slight fall in MAP in either group. The results suggest that elevated sympathetic activity is not a major contributor to the development of renal posttransplantation hypertension. spontaneously hypertensive rats; renal transplantation; sympathetic nervous system; tyrosine hydroxylase; guanabenz

Sodium homeostasis in transplanted rats with a spontaneously hypertensive rat kidney. Am J Physiol Regulatory Integrative Comp Physiol 279: R1099-R1104, 2000.--Recipients of a kidney from spontaneously hypertensive rats (SHR) but not from normotensive Wistar-Kyoto rats (WKY) develop posttransplantation hypertension. To investigate whether renal sodium retention precedes the development of posttransplantation hypertension in recipients of an SHR kidney on a standard sodium diet (0.6% NaCl), we transplanted SHR and WKY kidneys to SHR X WKY F1 hybrids, measured daily sodium balances during the first 12 days after removal of both native kidneys, and recorded mean arterial pressure (MAP) after 8 wk. Recipients of an SHR kidney (n = 12) retained more sodium than recipients of a WKY kidney (n = 12) (7.3 [+ or -] 10 vs. 4.0 [+ or -] 0.7 mmol, P [is less than] 0.05). MAP was 144 [+ or -] 6 mmHg in recipients of an SHR kidney and 106 [+ or -] 5 mmHg in recipients of a WKY kidney (P [is less than] 0.01). Modest sodium restriction (0.2% NaCl) in a further group of recipients of an SHR kidney (n = 10) did not prevent posttransplantation hypertension (MAP, 142 [+ or -] 4 mmHg). Urinary endothelin and urodilatin excretion rates were similar in recipients of an SHR and a WKY kidney. Transient excess sodium retention after renal transplantation may contribute to posttransplantation hypertension in recipients of an SHR kidney. hypertension; transplantation