The present study directly tested the hypothesis that deletion of the Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure by increasing the pressure natriuresis response in mice. Adult male and female, age-matched wild-type littermates (WT) and proximal tubule-specific NHE3-knockout mice (PT-Nhe3−/−) (n=6–16 per group) were studied for 1) basal phenotypes of electrolytes and pH, blood pressure, and kidney function, 2) the pressure natriuresis response using the mesenteric, celiac and abdominal arterial occlusion technique, and 3) the natriuretic responses to acute saline expansion (0.9% NaCl, 10% body wt., i.p.) or 2-week of 2% NaCl diet. Under basal conditions, PT-Nhe3−/− mice showed significantly lower systolic, diastolic, and mean arterial blood pressure (p<0.01) than WT mice (p<0.01). PT-Nhe3−/− mice also exhibited significantly greater diuretic (p<0.01) and natriuretic responses than WT mice (p<0.01), without altering 24 h fecal Na+ excretion, plasma pH, Na+, and bicarbonate levels. In response to increased renal perfusion pressure by 30 mmHg, the pressure natriuresis response increased 5-fold in WT mice (p<0.01), but it increased 8-fold in PT-Nhe3−/− mice (p<0.01). In response to 10% acute saline expansion or 2-week 2% NaCl diet, more pronounced natriuretic responses were demonstrated in PT-Nhe3−/− than WT mice (p<0.01). Our results support the scientific premise and physiological relevance that NHE3 in the proximal tubules plays an essential role in maintaining basal blood pressure homeostasis, and genetic deletion of NHE3 selectively in the proximal tubules of the kidney lowers blood pressure by increasing the pressure natriuretic response.

BackgroundStress and various stress hormones, including catecholamines and glucocorticoids, have recently been implicated in the pathogenesis of Alzheimer's disease (AD), which represents the greatest unresolved medical challenge in neurology. Angiotensin receptor blockers have shown benefits in AD and prone-to-AD animals. However, the mechanisms responsible for their efficacy remain unknown, and no studies have directly addressed the role of central angiotensin II (Ang II), a fundamental stress hormone, in the pathogenesis of AD. The present study focused on the role of central Ang II in amyloidogenesis, the critical process in AD neuropathology, and aimed to provide direct evidence for the role of this stress hormone in the pathogenesis of AD.Methodology/Principal FindingsIncreased central Ang II levels during stress response were modeled by intracerebroventricular (ICV) administration of graded doses of Ang II (6 ng/hr low dose, 60 ng/hr medium dose, and 600 ng/hr high dose, all delivered at a rate of 0.25 µl/hr) to male Sprague Dawley rats (280–310 g) via osmotic pumps. After 1 week of continuous Ang II infusion, the stimulation of Ang II type 1 receptors was accompanied by the modulation of amyloid precursor protein, α-, β-and γ-secretase, and increased β amyloid production. These effects could be completely abolished by concomitant ICV infusion of losartan, indicating that central Ang II played a causative role in these alterations.Conclusions/SignificanceCentral Ang II is essential to the stress response, and the results of this study suggest that increased central Ang II levels play an important role in amyloidogenesis during stress, and that central Ang II-directed stress prevention and treatment might represent a novel anti-AD strategy.

The present study directly tested the hypothesis that the NHE3 (Na + /H + exchanger 3) in the proximal tubules of the kidney is required for the development of Ang II (angiotensin II)-induced hypertension using PT- Nhe3 −/− (proximal tubule-specific NHE3 knockout) mice. Specifically, PT- Nhe3 −/− mice were generated using the SGLT2-Cre / Nhe3 loxlox approach, whereas Ang II-induced hypertension was studied in 12 groups (n=5–12 per group) of adult male and female wild-type (WT) and PT- Nhe3 −/− mice. Under basal conditions, systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were significantly lower in male and female PT- Nhe3 −/− than WT mice ( P <0.01). A high pressor, 1.5 mg/kg per day, intraperitoneal or a slow pressor dose of Ang II, 0.5 mg/kg per day, intraperitoneal for 2 weeks significantly increased systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure in male and female WT mice ( P <0.01), but the hypertensive response to Ang II was markedly attenuated in male and female PT- Nhe3 −/− mice ( P <0.01). Ang II impaired the pressure-natriuresis response in WT mice, whereas proximal tubule-specific deletion of NHE3 improved the pressure-natriuresis response in Ang II-infused PT- Nhe3 −/− mice ( P <0.01). AT 1 receptor blocker losartan completely blocked Ang II-induced hypertension in both WT and PT- Nhe3 −/− mice ( P <0.01). However, inhibition of nitric oxide synthase with L-N G -Nitroarginine methyl ester had no effect on Ang II-induced hypertension in WT or PT- Nhe3 −/− mice (not significant). Furthermore, Ang II-induced hypertension was significantly attenuated by an orally absorbable NHE3 inhibitor AVE0657. In conclusion, NHE3 in the proximal tubules of the kidney may be a therapeutical target in hypertension induced by Ang II or with increased NHE3 expression in the proximal tubules.

Edited by Barry HalliwellKeywords: Angiotensin II Glycogen synthase kinase 3b Tau Alzheimer disease a b s t r a c t Growing evidence suggests that Alzheimer disease (AD) origins in vascular lesions. As the crucial mediator of vascular pathology, angiotensin II-induced significant amyloid production in our laboratory, although amyloid neurotoxicity depended on phosphorylated tau (p-tau) in recent studies. In the present study, p-tau levels were significantly elevated by central angiotensin II via glycogen synthase kinase 3b (GSK 3b) and other tau kinases. Moreover, angiotensin II-induced cognitive impairment and tau phosphorylation was attenuated by losartan and a GSK 3b inhibitor. These findings implicate Ang II as a crucial mediator of AD pathology and a link between cardiovascular events and AD.

Background: Preclinical models have suggested a role for sex hormones in the development of glioblastoma multiforme (GBM). However, the impact of gender on the survival time of patients with GBM has not been fully understood. The objective of the present study was to clarify the association between gender and survival of patients with GBM by analyzing population-based data.Methods: We searched the Surveillance, Epidemiology, and End-Results database who were diagnosed with GBM between 2000 and 2008 and were treated with surgery. Five-year cancer specific survival data were obtained. Kaplan–Meier methods and multivariable Cox regression models were used to analyze long-term survival outcomes and risk factors.Results: A total of 6586 patients were identified; 61.5% were men and 38.5% were women. The 5-year cancer-specific survival (CSS) rates in the male and female groups were 6.8% and 8.3%, respectively (P=0.002 by univariate and P<0.001 by multivariate analysis). A stratified analysis showed that male patients always had the lowest CSS rate across localized cancer stage and different age subgroups.Conclusions: Gender has prognostic value for determining GBM risk. The role of sex hormones in the development of GBM warrants further investigation.

The renin-angiotensin system (RAS) is widely recognized as one of the most important vasoactive hormonal systems in the physiological regulation of blood pressure and the development of hypertension. This recognition is derived from, and supported by, extensive molecular, cellular, genetic, and pharmacological studies on the circulating (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (intracellular, mitochondrial, nuclear) RAS during last several decades. Now, it is widely accepted that circulating and local RAS may act independently or interactively, to regulate sympathetic activity, systemic and renal hemodynamics, body salt and fluid balance, and blood pressure homeostasis. However, there remains continuous debate with respect to the specific sources of intratubular and intracellular RAS in the kidney and other tissues, the relative contributions of the circulating RAS to intratubular and intracellular RAS, and the roles of intratubular compared with intracellular RAS to the normal control of blood pressure or the development of angiotensin II (ANG II)-dependent hypertension. Based on a lecture given at the recent XI International Symposium on Vasoactive Peptides held in Horizonte, Brazil, this article reviews recent studies using mouse models with global, kidney- or proximal tubule-specific overexpression (knockin) or deletion (knockout) of components of the RAS or its receptors. Although much knowledge has been gained from cell- and tissue-specific transgenic or knockout models, a unifying and integrative approach is now required to better understand how the circulating and local intratubular/intracellular RAS act independently, or with other vasoactive systems, to regulate blood pressure, cardiovascular and kidney function.

Background: Recent studies have discovered that functional connections are impaired among patients with Alzheimer's disease (AD), even at the preclinical stage. The cerebellum has been implicated as playing a role in cognitive processes. However, functional connectivity (FC) among cognitive sub-regions of the cerebellum in patients with AD and mild cognitive impairment (MCI) remains to be further elucidated.Objective: Our study aims to investigate the FC changes of the cerebellum among patients with AD and MCI, compared to healthy controls (HC). Additionally, we explored the role of cerebellum FC changes in the cognitive performance of all subjects.Materials: Resting-state functional magnetic resonance imaging (rs-fMRI) data from three different groups (28 AD patients, 26 MCI patients, and 30 HC) was collected. We defined cerebellar crus II and lobule IX as seed regions to assess the intragroup differences of cortico-cerebellar connectivity. Bias correlational analysis was performed to investigate the relationship between changes in FC and neuropsychological performance.Results: Compared to HC, AD patients had decreased FC within the caudate, limbic lobe, medial frontal gyrus (MFG), middle temporal gyrus, superior frontal gyrus, parietal lobe/precuneus, inferior temporal gyrus, and posterior cingulate gyrus. Interestingly, MCI patients demonstrated increased FC within inferior parietal lobe, and MFG, while they had decreased FC in the thalamus, inferior frontal gyrus, and superior frontal gyrus. Further analysis indicated that FC changes between the left crus II and the right thalamus, as well as between left lobule IX and the right parietal lobe, were both associated with cognitive decline in AD. Disrupted FC between left crus II and right thalamus, as well as between left lobule IX and right parietal lobe, was associated with attention deficit among subjects with MCI.Conclusion: These findings indicate that cortico-cerebellar FC in MCI and AD patients was significantly disrupted with different distributions, particularly in the default mode networks (DMN) and fronto-parietal networks (FPN) region. Increased activity within the fronto-parietal areas of MCI patients indicated a possible compensatory role for the cerebellum in cognitive impairment. Therefore, alterations in the cortico-cerebellar FC represent a novel approach for early diagnosis and a potential therapeutic target for early intervention.

Lesions of the cerebellum lead to motor and non-motor deficits by influencing cerebral cortex activity via cerebello-cortical circuits. It remains unknown whether the cerebello-cortical “disconnection” underlies motor and non-motor impairments both in the parkinsonian variant of multiple system atrophy (MSA-P) and Parkinson’s disease (PD). In this study, we investigated both the functional and effective connectivity of the cerebello-cortical circuits from resting-state functional magnetic resonance imaging (rs-fMRI) data of three groups (26 MSA-P patients, 31 PD patients, and 30 controls). Correlation analysis was performed between the causal connectivity and clinical scores. PD patients showed a weakened cerebellar dentate nucleus (DN) functional coupling in the posterior cingulate cortex (PCC) and inferior parietal lobe compared with MSA-P or controls. MSA-P patients exhibited significantly enhanced effective connectivity from the DN to PCC compared with PD patients or controls, as well as declined causal connectivity from the left precentral gyrus to right DN compared with the controls, and this value is significantly correlated with the motor symptom scores. Our findings demonstrated a crucial role for the cerebello-cortical networks in both MSA-P and PD patients in addition to striatal-thalamo-cortical (STC) networks and indicated that different patterns of cerebello-cortical loop degeneration are involved in the development of the diseases.