Effects of vitamin D or its analogues on the mortality of patients with chronic kidney disease: an updated systematic review and meta-analysis.

The objective of this study was to assess whether vitamin D (VD) treatment alters the overall all-cause and cardiovascular mortalities in a chronic kidney disease (CKD) population. We systematically searched PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials without language restriction, until the publication date of 22 February 2016. All related literatures that compared VD treatment with non-VD treatment and reported the mortality of patients with CKD (including those undergoing dialysis) were identified. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated by using the random- and fixed-effects models. Randomised controlled trials (RCTs) that used the intention-to-treat principle and observational studies (OSs) were analysed separately. For this study, 38 studies involving 223 429 patients (17 RCTs, n=1819 and 21 OSs, n=221610) were included. In the OSs, VD treatment was significantly associated with reductions in both all-cause and cardiovascular mortalities; however, such significant association was not found in the RCTs. The existing RCTs do not provide sufficient or precise evidence that VD supplementation affects the mortality of patients with CKD, although subsets of patients that could potentially benefit from VD treatment can be identified by using the existing data from the RCTs. Nevertheless, large-size RCTs are needed in the future to assess any potential differences in survival prospectively.

Superoxide anions involved in sympathoexcitation and pressor effects of salusin-ß in paraventricular nucleus in hypertensive rats.

AIMS: Salusin-ß in paraventricular nucleus (PVN) increases renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), heart rate (HR) and arginine vasopressin (AVP) release in hypertensive rats but not in normal rats. The present study was designed to investigate the downstream molecular mechanism of salusin-ß in the PVN in hypertension. METHOD: Renovascular hypertension was induced by two-kidney, one-clip (2K1C) in male SD rats. Acute experiments were carried out 4 weeks after 2K1C or sham operation under anaesthesia. RESULTS: MrgA1 mRNA expression and salusin-ß level in the PVN as well as plasma salusin-ß level were increased in 2K1C rats. Bilateral PVN microinjection of salusin-ß increased the RSNA, MAP and HR in 2K1C rats, which were abolished by the pre-treatment with polyethylene glycol-superoxide dismutase (PEG-SOD), the superoxide anion scavenger tempol, the NAD(P)H oxidase inhibitor apocynin or the protein kinase C (PKC) inhibitor chelerythrine chloride (CLC), but not affected by the AT1 receptor antagonist losartan, the Mas receptor antagonist A-779, the NOS inhibitor L-NAME or the GABAA and GABAB receptor antagonists gabazine+CGP-35348. Salusin-ß-induced increases in superoxide anion level and NAD(P)H oxidase activity in the PVN were abolished by the PVN pre-treatment with CLC. Salusin-ß increased AVP levels in rostral ventrolateral medulla and plasma, which were prevented by the pre-treatment with PEG-SOD, apocynin or CLC in 2K1C rats. Salusin-ß augmented the enhanced activity of PKC in the PVN in 2K1C rats. CONCLUSION: Protein kinase C-NAD(P)H oxidase-superoxide anions pathway in the PVN is involved in salusin-ß-induced sympathetic activation, pressor response and AVP release in renovascular hypertension.

Artificial microRNA interference targeting AT(1a) receptors in paraventricular nucleus attenuates hypertension in rats.

Excessive sympathetic activity has a crucial role in the initiation and progression of chronic structural alterations in the heart and vessels associated with hypertension. Angiotensin II type 1a receptors (AT(1a)R) in paraventricular nucleus (PVN) are involved in sympathetic overdrive and hypertension. The present study was designed to investigate the cardiovascular beneficial effects of the AT(1a)R gene silence in the PVN in hypertension. The PVN microinjection of recombinant adenoviral vectors expressing either artificial microRNA (amiRNA) targeting AT(1a) receptors (Ad-miR-AT(1a)) or control microRNA (Ad-miR-Con) were carried out in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. The vectors were labels with green fluorescent protein (GFP). The successful amiRNA interference was confirmed by the AT(1) receptors reduction and the GFP expression in the PVN. Significant depressor effects were observed from day 5 to day 20 after Ad-miR-AT(1a) treatment in SHR. Ad-miR-AT(1a) treatment decreased the ratio of left ventricular weight to body weight, cross-sectional areas of myocytes, myocardial fibrosis, media thickness, and the media/lumen ratio of the aorta and the mesenteric artery in SHR. The amiRNA interference reduced the basal sympathetic activity, cardiac sympathetic afferent reflex, plasma norepinephrine and plasma angiotensin II in SHR. These results indicate that amiRNA interference targeting AT(1a)R in the PVN decreases arterial blood pressure, blunts sympathetic activity and improves myocardial and vascular remodeling in SHR.

Inflammatory cytokines in paraventricular nucleus modulate sympathetic activity and cardiac sympathetic afferent reflex in rats.

AIM: This study was to determine the roles of inflammatory cytokines in paraventricular nucleus (PVN) in modulating sympathetic activity, blood pressure and cardiac sympathetic afferent reflex (CSAR). METHODS: Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in anaesthetized rats with bilateral sinoaortic denervation and vagotomy. The CSAR was evaluated by the RSNA response to epicardial application of bradykinin (BK). The levels of inflammatory cytokines were measured with ELISA. RESULTS: The PVN microinjection of pro-inflammatory cytokines (PIC), tumour necrosis factor (TNF)-α or interleukin (IL)-1ß, increased the baseline MAP and RSNA, and enhanced the CSAR. Anti-inflammatory cytokines (AIC), IL-4 or IL-13, in the PVN only increased the baseline MAP. In the rats pretreated with TNF-α or IL-1ß but not in the rats pretreated with IL-4 or IL-13, sub-response dose of angiotensin II caused significant increases in the MAP and RSNA and enhancement in the CSAR. AT(1) receptor antagonist losartan in the PVN attenuated the effects of angiotensin II, TNF-α and IL-1ß, but not the effects of IL-4 and IL-13. Stimulation of cardiac sympathetic afferents with epicardial application of BK increased the levels of TNF-α, IL-1ß but not IL-4 in the PVN. CONCLUSION: TNF-α or IL-1ß in the PVN increases blood pressure and sympathetic outflow and enhances the CSAR, which is partially dependent on the AT(1) receptors, while IL-4 or IL-13 in the PVN only increases blood pressure. There is a synergetic effect of Ang II with TNF-α or IL-1ß on blood pressure, sympathetic activity and CSAR.

Reactive oxygen species in rostral ventrolateral medulla modulate cardiac sympathetic afferent reflex in rats.

AIM: The aim of the present study was to investigate whether reactive oxygen species (ROS) in rostral ventrolateral medulla (RVLM) modulate cardiac sympathetic afferent reflex (CSAR) and the enhanced CSAR response caused by microinjection of angiotensin II (Ang II) into the paraventricular nucleus (PVN). METHODS: Under urethane and alpha-chloralose anaesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in sinoaortic-denervated and cervical-vagotomized rats. The CSAR was evaluated by the RSNA response to epicardial application of capsaicin (1.0 nmol). RESULTS: Bilateral RVLM microinjection of tempol (a superoxide anion scavenger) or polyethylene glycol-superoxide dismutase (PEG-SOD, an analogue of endogenous superoxide dismutase) attenuated the CSAR, but did not cause significant change in baseline RSNA and MAP. NAD(P)H oxidase inhibitors apocynin or phenylarsine oxide (PAO) also showed similar effects, but SOD inhibitor diethyldithio-carbamic acid (DETC) enhanced the CSAR and baseline RSNA, and increased the baseline MAP. Bilateral PVN microinjection of Ang II (0.3 nmol) enhanced the CSAR and increased RSNA and MAP, which was inhibited by the pre-treatment with RVLM administration of tempol, PEG-SOD, apocynin or PAO. The pre-treatment with DETC in the RVLM only showed a tendency in potentiating the CSAR response of Ang II in the PVN, but significantly potentiated the RSNA and MAP responses of Ang II. CONCLUSION: These results suggest that the NAD(P)H oxidase-derived ROS in the RVLM modulate the CSAR. The ROS in the RVLM is necessary for the enhanced CSAR response caused by Ang II in the PVN.