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1.  Hemodynamic and Hormonal Changes to Dual Renin Angiotensin System Inhibition in Experimental Hypertension 
Hypertension  2012;61(2):417-424.
We examined the antihypertensive effects of valsartan, aliskiren or both drugs combined on circulating, cardiac and renal components of the renin-angiotensin system (RAS) in congenic mRen2.Lewis hypertensive rats assigned to: vehicle (n=9), valsartan (via drinking water, 30 mg/kg/day; n=10), aliskiren (s.c. by osmotic mini-pumps, 50 mg/kg/day; n=10), or valsartan (30 mg/kg/day) combined with aliskiren (50 mg/kg/day; n=10). Arterial pressure and heart rate were measured by telemetry before and during two weeks of treatment; trunk blood, heart, urine and kidneys were collected for measures of RAS components. Arterial pressure and left ventricular weight/tibia length ratio were reduced by monotherapy of valsartan, aliskiren and further reduced by the combination therapy. Urinary protein excretion was reduced by valsartan and further reduced by the combination. The increases in plasma Ang II induced by valsartan were reversed by the treatment of aliskiren and partially suppressed by the combination. The decreases in plasma Ang-(1–7) induced by aliskiren recovered in the combination group. Kidney Ang-(1–12) was increased by the combination therapy while the increases in urinary creatinine mediated by valsartan were reversed by addition of aliskiren. The antihypertensive and antiproteinuric actions of the combined therapy were associated with marked worsening of renal parenchymal disease and increased peritubular fibrosis. The data show that despite improvements in the surrogate endpoints of blood pressure, ventricular mass and proteinuria, dual blockade of Ang II receptors and renin activity is accompanied by worsening of renal parenchymal disease reflecting a renal homeostatic stress response due to loss of tubuloglomerular feedback by Ang II.
doi:10.1161/HYPERTENSIONAHA.112.201889
PMCID: PMC3576205  PMID: 23232645
angiotensin-(1–12); aliskiren; arterial remodeling; direct renin inhibitors; urinary protein; valsartan
2.  Development of renal renin-expressing cells does not involve PDGF-B-PDGFR-β signaling 
Physiological Reports  2013;1(5):e00132.
Apart from their endocrine functions renin-expressing cells play an important functional role as mural cells of the developing preglomerular arteriolar vessel tree in the kidney. The recruitment of renin-expressing cells from the mesenchyme to the vessel wall is not well understood. Assuming that it may follow more general lines of pericyte recruitment to endothelial tubes we have now investigated the relevance of the platelet-derived growth factor (PDGF)-B-PDGFR-β signaling pathway in this context. We studied renin expression in kidneys lacking PDGFR-β in these cells and in kidneys with reduced endothelial PDGF-B expression. We found that expression of renin in the kidneys under normal and stimulated conditions was not different from wild-type kidneys. As expected, PDGFR-β immunoreactivity was found in mesangial, adventitial and tubulo-interstitial cells but not in renin-expressing cells. These findings suggest that the PDGF-B-PDGFR-β signaling pathway is not essential for the recruitment of renin-expressing cells to preglomerular vessel walls in the kidney.
doi:10.1002/phy2.132
PMCID: PMC3841059  PMID: 24303195
Mural cells; PDGF-B; PDGF-β receptor; pericyte; renin
3.  The efficacy of Li in bipolar disorder 
doi:10.2147/NDT.S48383
PMCID: PMC3713895  PMID: 23874097
4.  Pericytes synthesize renin 
World Journal of Nephrology  2013;2(1):11-16.
AIM: To investigate renin expression in pericytes during normal kidney development and after deletion of angiotensinogen, the precursor for all angiotensins.
METHODS: We examined the distribution of renin expressing cells by immunoshistochemistry in the interstitial compartment of wild type (WT) and angiotensinogen deficient (AGT -/-) mice at different developmental stages from embryonic day 18 (E18: WT, n = 4; AGT -/-, n = 5) and at day 1 (P1: WT, n = 5; AGT -/-, n = 5), 5 (P5: WT, n = 7; AGT -/-, n = 8), 10 (P10: WT, n = 3; AGT -/-, n = 5), 21 (P21: WT, n = 7; AGT -/-, n = 5), 45 (P45: WT, n = 3; AGT -/-, n = 3), and 70 (P70: WT, n = 2; AGT -/-, n = 2) of postnatal life. We quantified the number of pericytes positive for renin at all the developmental stages mentioned above and compared the results of AGT -/- mice to their WT counterparts.
RESULTS: In WT mice, renal interstitial pericytes synthesize renin in early life supporting a lineage relationship with renin cells in the vasculature. The number of pericytes positive for renin per area of 0.32 mm2 (density) in WT mice was maintained from fetal life till weaning age (E18 = 4.25 ± 0.63, P1 = 3.75 ± 0.48, P5 = 3.75 ± 0.48, P10 = 4 ± 0.71, P21 = 3.8 ± 0.58) and markedly decreased in adult life (P45 = 1.2 ± 0.37, P70 = 0.8 ± 0.20). On the other hand, in AGT -/- mice the density of pericytes expressing renin was not significantly different from WT mice at E18 and P1: E18 = 5.75 ± 0.50 vs 4.25 ± 0.63 (P = 0.106), P1 = 9.25 ± 3.50 vs 3.75 ± 0.48 (P = 0.175) but significantly increased from P5 till P70: P5 = 38.25 ± 5 vs 3.75 ± 0.48 (P = 0.0004), P10 = 173 ± 7.50 vs 4 ± 0.70 (P = 5.24567 × 10-7), P21 = 83 ± 6.70 vs 3.8 ± 0.58 (P = 2.97358 × 10-6), P45 = 49 ± 3.50 vs 1.2 ± 0.37 (P = 8.18274 x 10-7) and P70 = 17.8 ± 2.30 vs 0.8 ± 0.20 (P = 3.51151 × 10-5). The AGT -/- mice showed a marked increase in the number of pericytes per field studied starting from P5, reaching its peak at P10, and then a gradually decreasing until P70.
CONCLUSION: Interstitial pericytes synthesize renin during development and the number of renin-expressing pericytes increases in response to a homeostatic threat imposed early in life such as lack of angiotensinogen.
doi:10.5527/wjn.v2.i1.11
PMCID: PMC3782206  PMID: 24175260
Interstitium; Homeostasis; Angiotensinogen; Kidney; Renin angiotensin system; Development; Angiotensin deficiency; Gene deletion
5.  Could alterations in maternal plasma visfatin concentration participate in the phenotypes definition of preeclampsia and SGA? 
Objective
Women with preeclampsia and those who delivered a small-for-gestational-age (SGA) neonate share several mechanisms of disease, including chronic uteroplacental ischemia and failure of physiologic transformation of the spiral arteries. However, the clinical manifestation of these obstetrical syndromes is remarkably different. It has been proposed that an altered maternal metabolic state, as well as a unique circulating cytokines milieu, predispose women to develop either preeclampsia or SGA. Compelling evidence suggests that adipose tissue orchestrates both metabolic pathways and immunological responses via the production of adipokines. Visfatin is a novel adipocytokine with metabolic and immunomodulating properties. The objective of this study was to determine whether preeclampsia and SGA are associated with alterations in maternal circulating visfatin concentrations.
Methods
This cross-secitonal study included pregnant women in the following groups: (1) normal pregnancy (n = 158); (2) patients with preeclampsia (n = 43) of which 32 had an AGA and 11 had an SGA neonate; (3) patients without preeclampsia who delivered an SGA neonate (n = 55). Maternal plasma visfatin concentrations were measured by ELISA. Nonparametric tests and multiple linear regression analysis were used.
Results
(1) Women who delivered an SGA neonate had a higher median maternal plasma visfatin concentration than those with a normal pregnancy (20.0 ng/ml, interquartile range: 17.2-24.6 vs. 15.2 ng/ml, 12.1-19.2, respectively; P < 0.001) than those with preeclampsia (14.5 ng/ml, 12.5-18.7; P < 0.001); (2) the median maternal plasma visfatin concentration did not differ significantly between patients with preeclampsia and those with a normal pregnancy (P = 0.8); (3) among patients with preeclampsia, there was no significant difference in the median maternal plasma visfatin concentration between those with or without an SGA neonate (P = 0.5); (4) in a linear regression model, delivery of an SGA neonate and pregestational body mass index were independently associated with increased visfatin concentration after adjustment for confounding factors (maternal age, smoking, gestational age at blood collection and the presence of preeclampsia or SGA).
Conclusion
(1) Patients with SGA, but not those with preeclampsia, had a higher maternal plasma visfatin concentration than those with a normal pregnancy; (2) this finding suggests differential involvement of visfatin in SGA and preeclampsia; (3) we propose that changes in circulating maternal visfatin concentration may be implicated in the phenotypic definitions and distinction of preeclampsia and SGA.
doi:10.3109/14767050903301017
PMCID: PMC3554253  PMID: 19900033
Adipokine; pregnancy; fetal growth; metabolism; obesity
6.  276 A 4-Year Follow-up in Children With Moderate/Severe Asthma after Withdrawal 1 Year Omalizumab Treatment 
Background
Asthma guidelines include omalizumab in the step up management in those patients with severe non-controlled asthma despite the use of the inhaled corticosteroids (ICS) at the highest dose recommended and/or oral corticosteroids (OCS) courses. This communication describes the 4 year follow up of children with moderate/severe allergic asthma treated for 1 year with add-on omalizumab after discontinuation.
Methods
7 children (6 to <12 years) with moderate/severe uncontrolled asthma following strict inclusion/exclusion criteria. The patients completed a 1 year treatment with omalizumab according to the DBPC CIGE025 clinical study protocol. Four years follow up after discontinuation of the study medication was performed. It included clinical assessment, different asthma-related outcomes and lung function in outpatient hospital office
Results
All patients that received xolair during the study period achieved good asthma control and high dose ICS (mean dose fluticasone 500 mcg) were could be discontinued. Surprisingly, the 7 patients that received Xolair for one year were completely free of asthma symptoms during the first 3 years of follow up. They did not use any additional asthma medication. After the third year of follow up, only 2 out of 7 (28%) patients begun with persistent asthma symptoms and exacerbations. These patients have required rescue medication and then regular controller medication (budesonide 400 mcg). We could not identified any risk factor helping in predicting those who had symptoms relapsing. Lung function, number of exacerbation, number of hospitalization, eosinophilia, IgE levels or previous treatments with OCS
Conclusions
Most of these patients 5 out of 7 still remain asymptomatic 4 years after discontinuation Xolair without regular ICS treatment. They are still not using any controller medication only 2 patients had exacerbations and at present show persistent mild asthma controlled with medium ICS therapy. This follow up would generate the hypothesis that omalizumab could have a potential as a modifier of the natural history of asthma beyond the improvement of symptoms control in children with moderate/severe uncontrolled asthma. Further studies are needed to test this hypothesis.
doi:10.1097/01.WOX.0000412033.47007.6f
PMCID: PMC3512580
7.  151 International Survey on the Management of Allergic Rhinitis by Physicians and Patients (ISMAR): The Patients' View 
Background
Allergic Rhinitis (AR) is a worldwide spread illness and has an important impact on social life, sleep quality, school and work productivity and huge direct and indirect costs. Patient preference is becoming an important aspect in medical care. ISMAR was designed as the first-over global survey to identify differences in attitudes and preference in patients and physicians about AR. This study shows the patient's view.
Methods
ISMAR is an international, multicenter, non-interventional and cross-sectional study conducted in adults and children (≥ 6 years) with physician diagnosis- AR of at least 1 year of duration. Physicians recruited consecutive patients to whom the ISMAR questionnaire was administered. The study data collection was performed during a single visit. Other 2 additional documents (the investigator's questionnaire and Case Record Form) were also filled in.
Results
A total of 2776 patients from 11 countries were evaluated. Patient's demographics were the following: mean age 31 years, gender (F) 54%; urban residence (86.1%), suburban (6.6%) and rural (4.9%). The main co-morbidities were: sinusitis (50%), asthma (33%), conjunctivitis (36%), otitis (13%) and nasal polyps (11%). Nasal symptoms were associated to house-dust mites (84%), moulds (33%) animal dander (31%) and pollens (41%) exposure. At least one current treatment was received in 91%, and recommendation to avoid allergens or irritants in 93% of patients. 80% the patients had received oral anti-H1 antihistamines (OH1A), 66% intranasal corticosteroids (INC), 63% oral/intranasal decongestants and 14% sub-cutaneous specific immunotherapy (SCIT). The patients' preference was the following: oral route of administration, 51%; and intranasal route 28%. The patients' preference mediations were: OH1A, 76%; INC, 49%; and SCIT 12%. Main factors affecting treatment compliances were cost (32%), fear of Adverse Events reported (18%) and frequency of doses (34%). Taking into account patients' education, 85% of them received oral explanation on disease and only 51% written indications.
Conclusions
OH1A and INC were the most widely used treatments for rhinitis and were considered safe and effective. The majority of patients preferred the oral route. Written educational material given to patients is scarce. These might be taken into account to enhance treatment adherence and outcomes.
doi:10.1097/01.WOX.0000411908.12529.91
PMCID: PMC3512792
8.  150 International Survey on the Management of Allergic Rhinitis by Physicians and Patients (ISMAR). Physicians' View 
The World Allergy Organization Journal  2012;5(Suppl 2):S66-S67.
Background
Allergic Rhinitis (AR) is a worldwide spread disease and has an important impact on social life, sleep quality (SQ), school and work productivity and huge direct costs. ISMAR was designed to identify attitudes and medical trends among physicians managing AR in different parts of the world. This study presents the physicians´ view and attitudes.
Methods
ISMAR is an international, multicenter, non-interventional and cross-sectional study conducted in adults and children (≥6 years) with physicians-diagnosed AR from 11 countries (Egypt, Mexico, Brazil, Colombia, Guatemala, Iran, Venezuela, Argentina, Israel, Kuwait, United Arab Emirates). Doctors from 4 specialties were required in each country: (i) GPs/Family doctors/internists, (ii) pediatricians, (iii) allergologists/pulmonologists, and (iv) ENT. They were invited to participate in the study from master lists of physicians attending patients with AR in their respective countries and answered the Doctor Questionnaire that included questions about guidelines awareness, relevant AR symptoms, and preference for prescribing medication, among others.
Results
Two hundred and thirty four physicians participated in the study. Most of them were awared about ARIA (82.5%), GINA (71.4%). They followed guidelines recommandations to classify patients severity (84.2%) and for choosing the treatment accordingly (84.6%). Key symptoms to make AR diagnosis were: congestion (84.8%), sneezing (79.1%), anterior watery rhinorrhea (75.9%). SQ and AR severity were assessed mainly by clinical history (97.1% and 98%). The main reasons to prescribe medication were: symptom severity/frequency (97.9%), drug efficacy (85.9%) and safety (76.5%). Other less relevant raisons were: personal experience (65%), cost (55.1%) and frequency of dosages (54.7%). The preferred medications were oral antihistamines (OH1A) and intranasal corticosteroids (INC) [5 in a 0–5 scale]. Other treatments (oral decongestants, leukotriene antagonists, SCIT/SLIT), among others were considered as second level in preference.
Conclusions
Guidelines are well known and useful to physicians. Clinical history was the main way to evaluate the patient's sleep quality, classification, severity and election of treatment. Objective measures for assessment were scarcely used. OH1A and INC were the most widely recommended treatment for AR and were considered effective and safe.
doi:10.1097/01.WOX.0000411907.12529.75
PMCID: PMC3512960
9.  237 International Survey on the Management of Allergic Rhinitis by Physicians and Patients (ISMAR) 
Background
Allergic Rhinitis (AR) is an underappreciated disease considered to be trivial. The small group of patients taking medications for AR are usually seen by specialists. AR is under-diagnosed and under-treated with frequent non-adherence to treatment. There are a gap and unmet needs regarding the management of AR at global level. ISMAR was designed as the first-ever global, quantitative survey to ask to patients and physicians the same questions to identify differences in attitudes and opinions about the treatment of AR at global level with the goal of identifying barriers to optimal management and revealing limitations of currently available treatments.
Methods
An international, multicenter, non–interventional, cross-sectional study was conducted in adults or children (≥ 6 years). Physicians were selected at random from a master list provided by country and combining private and public practices. ISMAR was designed according to the most accepted epidemiological recommendations based on the successful experience of the WAO-GAPP survey on asthma. A questionnaire addressing patient profiles, diagnostic assessment, therapeutic decisions, and real-life management was answered. The questionnaire also asked about national/local features, medications availability/cost, laboratory test facilities, traditions, geographical constraints, among others. The participating physicians recruited consecutive patients with AR. Study data collection was performed during a single visit with 3 types of documents: Investigator's questionnaire, Case Record Form, Patient's questionnaire.
Results
Two-hundred and thirty four physicians were surveyed with a mean age of 49 years (28–69), 180 of them were males (76.9%). The type of medical practice was public sector 16.7%, private practice 41.9% and mixed 41.4%. Regarding medical specialty is a follows: GPs/family practitioners/internists (22.2%), allergologists/pulmonologists (35.9%), pediatricians (11.1%) and ENT specialist (30.3%). Physicians recruited 2776 patients with AR (Egypt, n = 500; Mexico, n = 418; Brazil, n = 351; Colombia, n = 223; Guatemala, n = 216; Iran, n = 207; Venezuela, n = 201; Argentina, n = 200; Israel, n = 176; Kuwait, n = 150; UAE, n = 134).
Conclusions
ISMAR has made possible the participation of physicians from eleven countries in different regions of the world that see AR patients. The doctors surveyed and the patients they recruited will give us the opportunity to gain insight about different aspects of the management of AR at global level.
doi:10.1097/01.WOX.0000411994.33545.2a
PMCID: PMC3513033
10.  271 Evaluation of Adverse Events Associated to Administration of Omalizumab 
The World Allergy Organization Journal  2012;5(Suppl 2):S105-S106.
Background
Anti IgE therapy is the ultimate therapeutic option for severe atopic conditions, not controlled by conventional treatment. Its efficacy and safety was described in several peer reviewed publications. Here we report on the events temporally related to the administration of almost 4 hundred doses of the only monoclonal Anti IgE antibody approved in our country for the treatment of severe asthma.
Methods
Descriptive retrospective analysis of clinical charts of patients receiving omalizumab because of Severe Uncontrolled Asthma, considering those events presented in the 72 hours after administration of it, which was not present before the procedure or as a concomitant condition of the patient. Vital signs, respiratory and cardiovascular evaluation, and dermatological inspection were performed in the hour after administration of corresponding doses. Patients having any kind of complaint were evaluated in unscheduled visits.
Results
384 doses of 150 mg omalizumab were given to from April 2007 to June 2011, to nine severe asthmatic patients. One of them received treatment for over 4 years, and two for over 3 years.
Conclusions
Our records from patients receiving omalizumab have not registered severe adverse events in almost four hundred doses given. The moderate adverse events of nausea and tachycardia resulted in discontinuation of treatment in this unique patient. Overall, omalizumab demonstrated a very acceptable safety profile in our patients.
doi:10.1097/01.WOX.0000412028.16513.92
PMCID: PMC3513165
11.  205 Allergy Training and Immunotherapy in Latin America: How Survey-Results Lead to a Regional Overview 
The World Allergy Organization Journal  2012;5(Suppl 2):S84-S85.
Background
In April 2011 a group of Latin American (LA) allergy experts, leaders in their countries in the area of immunotherapy, met in Cordoba, Argentina, to discuss how allergy and allergen-specific immunotherapy (ASIT) can be improved in the region. The need for a situational sketch was expressed.
Methods
A questionnaire on allergy training (AT), ASIT, extracts and legislation was sent out to 22 leaders in the field of nine LA countries to obtain an overview of the LA situation.
Results
Results are presented with descriptive statistics. All 22 questionnaires were returned (9 countries). AT in 56% of the surveyed LA countries is at the third-level of medical care, after a core-training of 2 to 3 years internal medicine or pediatrics; in 3 countries it is a second-level career and in one country there is no AT. Board certification with exam is only mandatory in a third of the countries; recertification being obtained without exam. Mostly, training is in general allergy; pediatric AT only exists in 2 countries. Both sublingual (SLIT, only in the form of drops) and subcutaneous (SCIT) immunotherapy are practiced in all countries, from the age of 3 years (mean, range 1–5 years) onward. As no strict legislation exists IT can be managed by non-allergists in 7/9 countries. Mixed extracts are used with mostly 3 to 5 allergens/vial (range 2 to 6-10 allergens/vial) and all countries have bacterial vaccine. SCIT extracts come from US and European (89%) and 56% local providers. SLIT extracts are almost exclusively from Europe (Spain), but in Argentine, Brazil, and Mexico also local SLIT extracts exist. There is rudimentary regulation concerning extract potency in 2 countries. IT is generally paid for by private patients. Insurance companies reimburse IT in 56% of the countries, the social security system in 33% and in one country selected third level governmental hospitals supply IT. Publications on adverse events with IT are starting to appear (3 countries) and 3 countries have their own guidelines on IT (one only in pediatrics).
Conclusions
A clearer picture where and how to improve AT and ASIT in LA has been obtained; however, unmet needs on ASIT are still pending.
doi:10.1097/01.WOX.0000411962.09782.2a
PMCID: PMC3513178
12.  Selective deletion of Connexin 40 in renin-producing cells impairs renal baroreceptor function and is associated with arterial hypertension 
Kidney international  2010;78(8):762-768.
Renin-producing juxtaglomerular cells are connected to each other and to endothelial cells of afferent arterioles by gap junctions containing Connexin 40 (Cx40), abundantly expressed by these two cell types. Here, we generated mice with cell-specific deletion of Cx40 in endothelial and in renin-producing cells, as its global deletion caused local dissociation of renin-producing cells from endothelial cells, renin hypersecretion, and hypertension. In mice lacking endothelial Cx40, the blood pressure, renin-producing cell distribution, and the control of renin secretion were similar to wild-type mice. In contrast, mice deficient for Cx40 in renin-producing cells were hypertensive and these cells were ectopically localized. Although plasma renin activity and kidney renin mRNA levels of these mice were not different from controls, the negative regulation of renin secretion by pressure was inverted to a positive feedback in kidneys lacking Cx40 in renin-producing cells. Thus, our findings show that endothelial Cx40 is not essential for the control of renin expression and/or release. Cx40 in renin-producing cells is required for their correct positioning in the juxtaglomerular area and the control of renin secretion by pressure.
doi:10.1038/ki.2010.257
PMCID: PMC3033195  PMID: 20686449
afferent arteriole; blood pressure; renal hypertension; renin angiotensin system
13.  Renal Failure in Mice with Gsα Deletion in Juxtaglomerular Cells 
American Journal of Nephrology  2010;32(1):83-94.
Background
Mice with deletion of Gsα in renin-producing cells (RC/FF mice) have been shown to have greatly reduced renin production and lack of responsiveness of renin secretion to acute stimuli. In addition, young RC/FF mice are hypotensive and have a vasopressin-resistant concentrating defect. In the present study we have determined the long-term effect on renal function, blood pressure, and renal pathology in this low renin and diuretic mouse model.
Methods and Results
Urine osmolarity of RC/FF mice was decreased in all age groups. GFR measured at 7, 14 and 20 weeks of age declined progressively. Single nephron GFR similarly declined while fractional proximal fluid absorption was maintained. Expression levels of extracellular matrix proteins (collagen I, IV and fibronectin) and α-smooth muscle actin were increased in kidneys of RC/FF mice at 20 weeks, and this was accompanied by focal segmental glomerulosclerosis and periglomerular interstitial fibrosis. RC/FF mice showed a progressive reduction of body weight, an increase in urine albumin excretion, and an increase of blood pressure with aging.
Conclusion
A chronic reduction of renin production in mice may be a risk factor in its own right, and does not protect renal function against the profibrotic influence of a chronically elevated urine flow.
doi:10.1159/000314635
PMCID: PMC2914394  PMID: 20551626
Renin-angiotension system; Renal failure; Pathology
14.  The renin phenotype: roles and regulation in the kidney 
Purpose of review
Renin cells are fundamental for the control of blood pressure, fluid electrolyte homeostasis and kidney development. This review discusses recent discoveries regarding the mechanisms that control the identity and fate of renin cells and their role in the maintenance of kidney architecture and function.
Recent findings
It is now established that cyclic AMP is a crucial factor for the regulation of the renin phenotype. Furthermore, additional factors such as microRNAs and gap junctions have recently emerged as key regulators for the maintenance and proper functioning of renin cells.
Summary
Experiments described in this review will hopefully raise new questions regarding the mechanisms that control the identity, plasticity and function of renin cells.
doi:10.1097/MNH.0b013e32833aff32
PMCID: PMC3079389  PMID: 20502328
cell identity; cell memory; cyclic AMP; microRNAs; plasticity
15.  Increased Renin Production in Mice with Deletion of PPARγ in Juxtaglomerular Cells 
Hypertension  2010;55(3):660-666.
We found recently that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome Proliferator-Activated Receptor-γ (PPARγ) stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARγ. The mouse renin gene is regulated by PPARγ through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPARγ knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPARγ would up-regulate mouse renin expression. Consistent with these observations knockdown of PPARγ increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPARγ on renin production in vivo we used a cre/lox system to generate double-transgenic mice with disrupted PPARγ locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPARγfl/fl mice). We provide evidence that PPARγ expression was effectively reduced in JG cells of RC-PPARγfl/fl mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPARγfl/fl than in littermate control RC-PPARγwt/wt mice. Renin mRNA levels and plasma renin concentration in RC-PPARγfl/fl mice were almost two fold higher than in littermate controls. Arterial blood pressure and pressure control of renal vascular resistance, which play decisive roles in the regulation of renin production were indistinguishable between RC-PPARγwt/wt and RC-PPARγfl/fl mice. These data demonstrate that the JG-specific PPARγ deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPARγ appears to be a relevant transcription factor for the control of renin gene in JG cells.
doi:10.1161/HYPERTENSIONAHA.109.138800
PMCID: PMC2907524  PMID: 20065157
Basic science; Gene expression/regulation; Hypertension (Kidney); Renin; Cell signaling
16.  Novel Mechanisms for the Control of Renin Synthesis and Release 
Current hypertension reports  2010;12(1):26-32.
Renin is the key regulated step in the enzymatic cascade that leads to angiotensin generation and the control of blood pressure and fluid/electrolyte homeostasis. In the adult unstressed animal, renin is synthesized and released by renal juxtaglomerular cells. However, when homeostasis is threatened, the number of cells that express and release renin increases and extends beyond the juxtaglomerular area; the result is an increase in circulating renin and the reestablishment of homeostasis. The increase in the number of renin cells, a process termed recruitment, is achieved by dedifferentiation and re-expression of renin in cells derived from the renin lineage. The mechanisms that regulate the related processes of reacquisition of the renin phenotype, renin synthesis, and renin release are beginning to be understood. Numerous studies point to cAMP as a central common factor for the regulation of renin phenotype. In addition, we are seeing the emergence of gap junctions and microRNAs as new and promising avenues for a more complete understanding of the complex regulation of the renin cell.
doi:10.1007/s11906-009-0080-z
PMCID: PMC2861778  PMID: 20425155
Juxtaglomerular cells; cAMP; Plasticity; Cell identity; MicroRNAs; Homeostasis
17.  Who and where is the renal baroreceptor?: the connexin hypothesis 
Kidney international  2009;75(5):460-462.
Gap junctions are emerging as a fundamental mechanism for the control of renin synthesis and release. Connexin40 is prominent in juxtaglomerular cells. When missing, it results in hyperreninemia and hypertension. Schweda et al. offer exciting data demonstrating that connexin45, a connexin with different biophysical properties, can replace connexin40 functions related to the control of renin.
doi:10.1038/ki.2008.536
PMCID: PMC3025775  PMID: 19219002
18.  Quality of life in multiple sclerosis is associated with lesion burden and brain volume measures 
Neurology  2009;72(20):1760-1765.
Background:
Health-related quality of life (HRQOL) is reduced in multiple sclerosis (MS). It is unclear whether HRQOL is associated with white matter lesion burden or measures of brain atrophy.
Methods:
A cross-sectional baseline analysis of 507 patients with MS in a prospective cohort study at the University of California, San Francisco was performed. Multivariate linear regression models were used to determine whether MRI measures were associated with the Emotional Well-Being and Thinking/Fatigue subscale scores of the Functional Assessment in Multiple Sclerosis, a validated HRQOL measure in MS. The difference in each MRI metric associated with a minimal clinically important difference in each HRQOL subscale was calculated.
Results:
Higher T1 lesion load (15 mL; p = 0.024), normalized T1 lesion volume (20 mL; p = 0.016), or T2 lesion load (25 mL; p = 0.028) was associated with worse scores for Emotional Well-Being. Meaningfully lower scores on this subscale were correlated with lower normalized gray matter volume (118 mL; p = 0.037). Reduced Thinking/Fatigue scores were associated with higher normalized T1 lesion volume (21 mL; p = 0.024), or T2 lesion load (22 mL; p = 0.010) and with lower normalized gray matter (87 mL; p = 0.004), white matter (85 mL; p = 0.025), or brain parenchymal (98 mL; p = 0.001) volume.
Conclusions:
Aspects of health-related quality of life (HRQOL) in multiple sclerosis are associated with MRI evidence of white matter lesions and brain atrophy. These findings strengthen the argument for the use of HRQOL outcome measures in trials and suggest that lesion burden on conventional MRI is important for HRQOL.
GLOSSARY
= clinically isolated syndrome;
= disease-modifying therapy;
= Expanded Disability Status Scale;
= Emotional Well-Being;
= Functional Assessment in Multiple Sclerosis;
= field of view;
= health-related quality of life;
= interquartile range;
= inversion recovery spoiled gradient-recalled;
= Paced Auditory Serial Addition Test;
= primary progressive multiple sclerosis;
= progressive relapsing multiple sclerosis;
= multiple sclerosis;
= Multiple Sclerosis Functional Composite;
= normalized brain parenchymal volume;
= number of excitations;
= normalized gray matter volume;
= normalized T1 lesion volume;
= normalized white matter volume;
= relapsing–remitting multiple sclerosis;
= secondary progressive multiple sclerosis;
= echo time;
= inversion time;
= Thinking/Fatigue;
= repetition time;
= University of California, San Francisco.
doi:10.1212/WNL.0b013e3181a609f8
PMCID: PMC2683738  PMID: 19451531
19.  Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane 
BJA: British Journal of Anaesthesia  2009;102(3):355-360.
Background
Inhaled anaesthetics (IAs) produce multiple dose-dependent behavioural effects including amnesia, hypnosis, and immobility in response to painful stimuli that are mediated by distinct anatomical, cellular, and molecular mechanisms. Amnesia is produced at lower anaesthetic concentrations compared with hypnosis or immobility. Nicotinic acetylcholine receptors (nAChRs) modulate hippocampal neural network correlates of memory and are highly sensitive to IAs. Activation of hippocampal nAChRs stimulates the release of norepinephrine (NE), a neurotransmitter implicated in modulating hippocampal synaptic plasticity. We tested the hypothesis that IAs disrupt hippocampal synaptic mechanisms critical to memory by determining the effects of isoflurane on NE release from hippocampal nerve terminals.
Methods
Isolated nerve terminals prepared from adult male Sprague–Dawley rat hippocampus were radiolabelled with [3H]NE and either [14C]GABA or [14C]glutamate and superfused at 37°C. Release evoked by a 2 min pulse of 100 µM nicotine or 5 µM 4-aminopyridine was evaluated in the presence or absence of isoflurane and/or selective antagonists.
Results
Nicotine-evoked NE release from rat hippocampal nerve terminals was nAChR- and Ca2+-dependent, involved both α7 and non-α7 subunit-containing nAChRs, and was partially dependent on voltage-gated Na+ channel activation based on sensitivities to various antagonists. Isoflurane inhibited nicotine-evoked NE release (IC50=0.18 mM) more potently than depolarization-evoked NE release (IC50=0.27 mM, P=0.014), consistent with distinct presynaptic mechanisms of IA action.
Conclusions
Inhibition of hippocampal nAChR-dependent NE release by subanaesthetic concentrations of isoflurane supports a role in IA-induced amnesia.
doi:10.1093/bja/aen387
PMCID: PMC2642653  PMID: 19189985
anaesthetics volatile, isoflurane; brain, anaesthesia, molecular effects; brain, hippocampus; ions, ion channels, ligand-gated; nerve, neurotransmitters
20.  Oral phaeohyphomycosis 
Journal of Clinical Pathology  2007;60(2):204-205.
This is the first description of solitary phaeohyphomycosis affecting the mucosal surface. The lesion developed in the inferior lip of a 57‐year‐old woman. After surgical resection, histopathological examination evidenced characteristic brownish fungal structures within granulomatous–purulent inflammation. Amplification and sequencing of rDNA obtained from paraffin‐embedded tissue identified Alternaria species, as the causative agent.
doi:10.1136/jcp.2005.035808
PMCID: PMC1860624  PMID: 17264246
21.  Genotype–Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures 
Brain  2009;132(1):250-259.
Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype–phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via 1HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm3; P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention.
doi:10.1093/brain/awn301
PMCID: PMC2638695  PMID: 19022862
multiple sclerosis; HLA; spectroscopy; brain atrophy; cognition
22.  Changes in plasma levels of fat‐derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2006;65(9):1198-1201.
Background
Rheumatoid arthritis is a chronic autoimmune inflammatory condition characterised by polyarthritis and severe change in body mass and neuroendocrine environment.
Objectives
To investigate plasma levels of adipocytokines (leptin, adiponectin, visfatin and resistin) in patients with rheumatoid arthritis and to compare them with levels in healthy controls.
Methods
Adiponectin, resistin, visfatin and leptin concentrations were measured in 31 patients with rheumatoid arthritis and 18 healthy controls by using specific enzyme‐linked immunosorbent assays.
Results
Patients with rheumatoid arthritis showed considerably higher plasma levels of leptin, adiponectin and visfatin than healthy controls. No marked difference was observed in resistin levels between patients and controls.
Conclusion
A marked increase in plasma levels of leptin, adiponectin and visfatin was noted in patients with rheumatoid arthritis, whereas resistin levels were similar to those observed in healthy controls. Coordinated roles for adiponectin, leptin and visfatin are suggested in the modulation of the inflammatory environment in patients with rheumatoid arthritis, whereas the lack of modulation in resistin levels is predictive of an irrelevant role for this peptide, suggesting that resistin level is probably not one of the main signals associated with the pathogenesis of this disease.
doi:10.1136/ard.2005.046540
PMCID: PMC1798289  PMID: 16414972
23.  Adiponectin Multimers in Normal Pregnancy 
Objective
Adiponectin is an anti-diabetic, anti-atherogenic, anti-inflammatory and angiogenic adipokine that circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. The aim of this study was to determine whether there are changes in adiponectin multimers in pregnancy and as a function of maternal weight.
Study design
In this cross-sectional study, serum concentrations of total, HMW, MMW and LMW adiponectin were determined in women included in three groups: 1) normal pregnant women of normal body mass index (BMI) (n=466); 2) overweight/obese pregnant women (BMI ≥25; n=257); and 3) non-pregnant women of normal weight (n=40). Blood samples were collected once from each pregnant woman between 11 and 42 weeks of gestation. Serum adiponectin multimers concentrations were determined by ELISA. Non-parametric statistics were used for analysis.
Results
1) The median HMW adiponectin concentration and the median HMW/Total adiponectin ratio were significantly higher and the median LMW adiponectin concentration was significantly lower in pregnant than in non-pregnant women; 2) among pregnant women, the median serum concentration of total, HMW and MMW adiponectin was significantly higher in normal weight women than in overweight/obese patients; 3) HMW adiponectin was the most prevalent multimer in maternal serum regardless of gestational age or BMI status; 4) there were no significant differences in the median concentration of total, MMW, LMW adiponectin, and their relative distribution with advancing gestation.
Conclusion
Human pregnancy is characterized by quantitative and qualitative changes in adiponectin multimers, especially of the most active isoform, HMW adiponectin.
doi:10.1080/14767050802266881
PMCID: PMC2729195  PMID: 19031276
Adiponectin; Adipokines; Pregnancy; High molecular weight (HMW) adiponectin; Medium molecular weigh (MMW) adiponectin; Low molecular weight (LMW) adiponectin; BMI
24.  TNFA and IL10 Gene Polymorphisms are not Associated with Periodontitis in Brazilians 
The Open Dentistry Journal  2009;3:184-190.
IL-10 and TNF-α are cytokines that have complex and opposing roles in the inflammatory responses. G/A polymorphisms at position –1082 of IL10 and –308 of TNFA genes have been reported to influence the expression of IL-10 and TNF-α, respectively. The aim of this study was to investigate the association between the IL10 (-1082) and TNFA (- 308) gene polymorphisms with different clinical forms or severity of periodontitis in a sample of Brazilian individuals. DNA was obtained from oral swabs of 165 Brazilian individuals, which were divided into three groups: individuals with chronic periodontitis, aggressive periodontitis and individuals without clinical evidence of periodontitis. Evaluation of IL10 and TNFA polymorphisms was performed by RFLP analysis. Statistical analysis of data was performed using the χ2 likelihood ratio and Fisher`s exact test. No significant differences in the genotype and allele distribution of either IL10 or TNFA were observed among individuals with different clinical forms or with different degrees of severity of periodontitis. Moreover, combined analysis of IL10 and TNFA polymorphisms did not show any association with periodontal status. As conclusion, the IL10 and TNFA gene promoter polymorphisms investigated are not associated with different clinical forms of periodontitis or with severity of the disease in the Brazilian population polymorphisms.
doi:10.2174/1874210600903010184
PMCID: PMC2745565  PMID: 19771178
IL-10; TNF-alpha; periodontitis; polymorphism.
25.  Oxford textbook of public health, 4th edn 
doi:10.1136/jech.56.10.800
PMCID: PMC1732040

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