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1.  Climate Change and Population Growth in Timor Leste: Implications for Food Security 
Ambio  2012;41(8):823-840.
The climate in Timor Leste (East Timor) is predicted to become about 1.5 °C warmer and about 10 % wetter on average by 2050. By the same year, the population is expected to triple from 1 to 2.5–3 million. This article maps the predicted changes in temperature and rainfall and reviews the implications of climate change and population growth on agricultural systems. Improved cultivars of maize, rice, cassava, sweet potato and peanuts with high yield performance have been introduced, but these will need to be augmented in the future with better adapted cultivars and new crops, such as food and fodder legumes and new management practices. The requirements for fertilizers to boost yields and terracing and/or contour hedgerows to prevent soil erosion of steeply sloping terrain are discussed. Contour hedges can also be used for fodder for improved animal production to provide protein to reduce malnutrition.
doi:10.1007/s13280-012-0287-0
PMCID: PMC3492559  PMID: 22569843
Timor Leste; Climate change; Population increase; Shifting agriculture; Food security; Small-holder farmers
2.  Apolipoprotein(a) acts as a chemorepellent to human vascular smooth muscle cells via integrin αVβ3 and RhoA/ROCK-mediated mechanisms☆ 
Graphical abstract
Highlights
•Acute application of apo(a) to smooth muscle cells induced chemorepulsion.•Chronic application (>24 h) induced stress fibre formation and cell spreading.•Effects of apo(a) were mediated by integrin αVβ3, tyrosine kinases and RhoA/ROCK.•Apo(a) impaired SMC motility which potentially contributes to vascular dysfunction.
Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease. Vascular smooth muscle cell (SMC) motility and plasticity, functions that are influenced by environmental cues, are vital to adaptation and remodelling in vascular physiology and pathophysiology. Lp(a) is reportedly damaging to SMC function via unknown molecular mechanisms. Apolipoprotein(a) (apo(a)), a unique glycoprotein moiety of Lp(a), has been demonstrated as its active component. The aims of this study were to determine functional effects of recombinant apo(a) on human vascular SMC motility and explore the underlying mechanism(s). Exposure of SMC to apo(a) in migration assays induced a potent, concentration-dependent chemorepulsion that was RhoA and integrin αVβ3-dependent, but transforming growth factor β-independent. SMC manipulation through RhoA gene silencing, Rho kinase inhibition, statin pre-treatment, αVβ3 neutralising antibody and tyrosine kinase inhibition all markedly inhibited apo(a)-mediated SMC migration. Our data reveal unique and potent activities of apo(a) that may negatively influence SMC remodelling in cardiovascular disease. Circulating levels of Lp(a) are resistant to lipid-lowering strategies and hence a greater understanding of the mechanisms underlying its functional effects on SMC may provide alternative therapeutic targets.
doi:10.1016/j.biocel.2013.05.021
PMCID: PMC3731554  PMID: 23726972
Ao, aortic; α-SMA, alpha smooth muscle actin; apo(a), apolipoprotein(a); DMEM, Dulbecco's modified eagle medium; ERK, extracellular signal-regulated kinase; FCS, foetal calf serum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HP, high power; Lp(a), lipoprotein(a); MAPK, mitogen activated protein kinase; NFκB, nuclear factor kappa B; PDGF, platelet-derived growth factor-BB; ROCK, Rho kinase; SV, saphenous vein; SMC, smooth muscle cell; TGFβ, transforming growth factor beta; Lipoprotein(a); Vascular smooth muscle cells; Migration; RhoA; Remodelling
3.  Function and fate of myofibroblasts after myocardial infarction 
The importance of cardiac fibroblasts in the regulation of myocardial remodelling following myocardial infarction (MI) is becoming increasingly recognised. Studies over the last few decades have reinforced the concept that cardiac fibroblasts are much more than simple homeostatic regulators of extracellular matrix turnover, but are integrally involved in all aspects of the repair and remodelling of the heart that occurs following MI. The plasticity of fibroblasts is due in part to their ability to undergo differentiation into myofibroblasts. Myofibroblasts are specialised cells that possess a more contractile and synthetic phenotype than fibroblasts, enabling them to effectively repair and remodel the cardiac interstitium to manage the local devastation caused by MI. However, in addition to their key role in cardiac restoration and healing, persistence of myofibroblast activation can drive pathological fibrosis, resulting in arrhythmias, myocardial stiffness and progression to heart failure. The aim of this review is to give an appreciation of both the beneficial and detrimental roles of the myofibroblast in the remodelling heart, to describe some of the major regulatory mechanisms controlling myofibroblast differentiation including recent advances in the microRNA field, and to consider how this cell type could be exploited therapeutically.
doi:10.1186/1755-1536-6-5
PMCID: PMC3599637  PMID: 23448358
Myofibroblasts; Heart; Myocardial infarction; Remodelling; Fibrosis
4.  p38 MAPK alpha mediates cytokine-induced IL-6 and MMP-3 expression in human cardiac fibroblasts 
Highlights
► The p38 MAPK signaling pathway regulates cardiac remodeling. ► Human cardiac fibroblasts express the α, γ and δ subtypes of p38 MAPK. ► IL-1 selectively stimulates p38α and p38γ activation. ► p38α is important for IL-1-induced IL-6 and MMP-3 expression in cardiac fibroblasts.
Pre-clinical studies suggest that the p38 MAPK signaling pathway plays a detrimental role in cardiac remodeling, but its role in cardiac fibroblast (CF) function is not well defined. We aimed to identify the p38 MAPK subtypes expressed by human CF, study their activation in response to proinflammatory cytokines, and determine which subtypes were important for expression of specific cytokines and matrix metalloproteinases (MMPs).
Quantitative real-time RT-PCR analysis of mRNA levels in human CF cultured from multiple patients revealed a consistent pattern of expression with p38α being most abundant, followed by p38γ, then p38δ and only low expression of p38β (3% of p38α mRNA levels). Immunoblotting confirmed marked protein expression of p38α, γ and δ, with little or no expression of p38β. Phospho-ELISA and combined immunoprecipitation/immunoblotting techniques demonstrated that the proinflammatory cytokines IL-1α and TNFα selectively activated p38α and p38γ, but not p38δ. Selective p38α siRNA gene silencing reduced IL-1α-induced IL-6 and MMP-3 mRNA expression and protein secretion, without affecting IL-1α-induced IL-1β and MMP-9 mRNA expression.
In conclusion, human CF express the α, γ and δ subtypes of p38 MAPK, and the α subtype is important for IL-1α-induced IL-6 and MMP-3 expression in this cell type.
doi:10.1016/j.bbrc.2012.11.071
PMCID: PMC3573232  PMID: 23206705
p38 MAPK; Cardiac fibroblasts; Heart; Interleukin; Matrix metalloproteinase
5.  A Systematic Review and Meta-Analysis of Utility-Based Quality of Life in Chronic Kidney Disease Treatments 
PLoS Medicine  2012;9(9):e1001307.
Melanie Wyld and colleagues examined previously published studies to assess pooled utility-based quality of life of the various treatments for chronic kidney disease. They conclude that the highest utility was for kidney transplants, with home-based automated peritoneal dialysis being second.
Background
Chronic kidney disease (CKD) is a common and costly condition to treat. Economic evaluations of health care often incorporate patient preferences for health outcomes using utilities. The objective of this study was to determine pooled utility-based quality of life (the numerical value attached to the strength of an individual's preference for a specific health outcome) by CKD treatment modality.
Methods and Findings
We conducted a systematic review, meta-analysis, and meta-regression of peer-reviewed published articles and of PhD dissertations published through 1 December 2010 that reported utility-based quality of life (utility) for adults with late-stage CKD. Studies reporting utilities by proxy (e.g., reported by a patient's doctor or family member) were excluded.
In total, 190 studies reporting 326 utilities from over 56,000 patients were analysed. There were 25 utilities from pre-treatment CKD patients, 226 from dialysis patients (haemodialysis, n = 163; peritoneal dialysis, n = 44), 66 from kidney transplant patients, and three from patients treated with non-dialytic conservative care. Using time tradeoff as a referent instrument, kidney transplant recipients had a mean utility of 0.82 (95% CI: 0.74, 0.90). The mean utility was comparable in pre-treatment CKD patients (difference = −0.02; 95% CI: −0.09, 0.04), 0.11 lower in dialysis patients (95% CI: −0.15, −0.08), and 0.2 lower in conservative care patients (95% CI: −0.38, −0.01). Patients treated with automated peritoneal dialysis had a significantly higher mean utility (0.80) than those on continuous ambulatory peritoneal dialysis (0.72; p = 0.02). The mean utility of transplant patients increased over time, from 0.66 in the 1980s to 0.85 in the 2000s, an increase of 0.19 (95% CI: 0.11, 0.26). Utility varied by elicitation instrument, with standard gamble producing the highest estimates, and the SF-6D by Brazier et al., University of Sheffield, producing the lowest estimates. The main limitations of this study were that treatment assignments were not random, that only transplant had longitudinal data available, and that we calculated EuroQol Group EQ-5D scores from SF-36 and SF-12 health survey data, and therefore the algorithms may not reflect EQ-5D scores measured directly.
Conclusions
For patients with late-stage CKD, treatment with dialysis is associated with a significant decrement in quality of life compared to treatment with kidney transplantation. These findings provide evidence-based utility estimates to inform economic evaluations of kidney therapies, useful for policy makers and in individual treatment discussions with CKD patients.
Editors' Summary
Background
Ill health can adversely affect an individual's quality of life, particularly if caused by long-term (chronic) conditions, such as chronic kidney disease—in the United States alone, 23 million people have chronic kidney disease, of whom 570,000 are treated with dialysis or kidney transplantation. In order to measure the cost-effectiveness of interventions to manage medical conditions, health economists use an objective measurement known as quality-adjusted life years. However, although useful, quality-adjusted life years are often criticized for not taking into account the views and preferences of the individuals with the medical conditions. A measurement called a utility solves this problem. Utilities are a numerical value (measured on a 0 to 1 scale, where 0 represents death and 1 represents full health) of the strength of an individual's preference for specified health-related outcomes, as measured by “instruments” (questionnaires) that rate direct comparisons or assess quality of life.
Why Was This Study Done?
Previous studies have suggested that, in people with chronic kidney disease, quality of life (as measured by utility) is higher in those with a functioning kidney transplant than in those on dialysis. However, currently, it is unclear whether the type of dialysis affects quality of life: hemodialysis is a highly technical process that directly filters the blood, usually must be done 2–4 times a week, and can only be performed in a health facility; peritoneal dialysis, in which fluids are infused into the abdominal cavity, can be done nightly at home (automated peritoneal dialysis) or throughout the day (continuous ambulatory peritoneal dialysis). In this study, the researchers reviewed and assimilated all of the available evidence to investigate whether quality of life in people with chronic kidney disease (as measured by utility) differed according to treatment type.
What Did the Researchers Do and Find?
The researchers did a comprehensive search of 11 databases to identify all relevant studies that included people with severe (stage 3, 4, or 5) chronic kidney disease, their form of treatment, and information on utilities—either reported directly, or included in quality of life instruments (SF-36), so the researchers could calculate utilities by using a validated algorithm. The researchers also recorded the prevalence rates of diabetes in study participants. Then, using statistical models that adjusted for various factors, including treatment type and the method of measuring utilities, the researchers were able to calculate the pooled utilities of each form of treatment for chronic kidney disease.
The researchers included 190 studies, representing over 56,000 patients and generating 326 utility estimates, in their analysis. The majority of utilities (77%) were derived through the SF-36 questionnaire via calculation. Of the 326 utility estimates, 25 were from patients pre-dialysis, 226 were from dialysis patients (the majority of whom were receiving hemodialysis), 66 were from kidney transplant patients, and three were from conservative care patients. The researchers found that the highest average utility was for those who had renal transplantation, 0.82, followed by the pre-dialysis group (0.80), dialysis patients (0.71), and, finally, patients receiving conservative care (0.62). When comparing the type of dialysis, the researchers found that there was little difference in utility between hemodialysis and peritoneal dialysis, but patients using automated peritoneal dialysis had, on average, a higher utility (0.80) than those treated with continuous ambulatory peritoneal dialysis (0.72). Finally, the researchers found that patient groups with diabetes had significantly lower utilities than those without diabetes.
What Do These Findings Mean?
These findings suggest that in people with chronic kidney disease, renal transplantation is the best treatment option to improve quality of life. For those on dialysis, home-based automated peritoneal dialysis may improve quality of life more than the other forms of dialysis: this finding is important, as this type of dialysis is not as widely used as other forms and is also cheaper than hemodialysis. Furthermore, these findings suggest that patients who choose conservative care have significantly lower quality of life than patients treated with dialysis, a finding that warrants further investigation. Overall, in addition to helping to inform economic evaluations of treatment options, the information from this analysis can help guide clinicians caring for patients with chronic kidney disease in their discussions about possible treatment options.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001307.
Information about chronic kidney disease is available from the National Kidney Foundation and MedlinePlus
Wikipedia gives information on general utilities (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001307
PMCID: PMC3439392  PMID: 22984353
6.  β-Aminobutyric acid increases abscisic acid accumulation and desiccation tolerance and decreases water use but fails to improve grain yield in two spring wheat cultivars under soil drying 
Journal of Experimental Botany  2012;63(13):4849-4860.
A pot experiment was conducted to investigate the effect of the non-protein amino acid, β-aminobutyric acid (BABA), on the homeostasis between reactive oxygen species (ROS) and antioxidant defence during progressive soil drying, and its relationship with the accumulation of abscisic acid (ABA), water use, grain yield, and desiccation tolerance in two spring wheat (Triticum aestivum L.) cultivars released in different decades and with different yields under drought. Drenching the soil with 100 µM BABA increased drought-induced ABA production, leading to a decrease in the lethal leaf water potential (Ψ) used to measure desiccation tolerance, decreased water use, and increased water use efficiency for grain (WUEG) under moderate water stress. In addition, at severe water stress levels, drenching the soil with BABA reduced ROS production, increased antioxidant enzyme activity, and reduced the oxidative damage to lipid membranes. The data suggest that the addition of BABA triggers ABA accumulation that acts as a non-hydraulic root signal, thereby closing stomata, and reducing water use at moderate stress levels, and also reduces the production of ROS and increases the antioxidant defence enzymes at severe stress levels, thus increasing the desiccation tolerance. However, BABA treatment had no effect on grain yield of wheat when water availability was limited. The results suggest that there are ways of effectively priming the pre-existing defence pathways, in addition to genetic means, to improve the desiccation tolerance and WUEG of wheat.
doi:10.1093/jxb/ers164
PMCID: PMC3428007  PMID: 22859677
Abscisic acid; β-aminobutyric acid; desiccation resistance; non-hydraulic signals; reactive oxygen species; transpiration efficiency for grain; Triticum aestivum L.; water use efficiency for grain
7.  Patient access to complex chronic disease records on the Internet 
Background
Access to medical records on the Internet has been reported to be acceptable and popular with patients, although most published evaluations have been of primary care or office-based practice. We tested the feasibility and acceptability of making unscreened results and data from a complex chronic disease pathway (renal medicine) available to patients over the Internet in a project involving more than half of renal units in the UK.
Methods
Content and presentation of the Renal PatientView (RPV) system was developed with patient groups. It was designed to receive information from multiple local information systems and to require minimal extra work in units. After piloting in 4 centres in 2005 it was made available more widely. Opinions were sought from both patients who enrolled and from those who did not in a paper survey, and from staff in an electronic survey. Anonymous data on enrolments and usage were extracted from the webserver.
Results
By mid 2011 over 17,000 patients from 47 of the 75 renal units in the UK had registered. Users had a wide age range (<10 to >90 yrs) but were younger and had more years of education than non-users. They were enthusiastic about the concept, found it easy to use, and 80% felt it gave them a better understanding of their disease. The most common reason for not enrolling was being unaware of the system. A minority of patients had security concerns, and these were reduced after enrolling.
Staff responses were also strongly positive. They reported that it aided patient concordance and disease management, and increased the quality of consultations with a neutral effect on consultation length. Neither patient nor staff responses suggested that RPV led to an overall increase in patient anxiety or to an increased burden on renal units beyond the time required to enrol each patient.
Conclusions
Patient Internet access to secondary care records concerning a complex chronic disease is feasible and popular, providing an increased sense of empowerment and understanding, with no serious identified negative consequences. Security concerns were present but rarely prevented participation. These are powerful reasons to make this type of access more widely available.
doi:10.1186/1472-6947-12-87
PMCID: PMC3438097  PMID: 22867441
8.  Modulatory effect of interleukin-1α on expression of structural matrix proteins, MMPs and TIMPs in human cardiac myofibroblasts: Role of p38 MAP kinase 
Matrix Biology  2010;29(7-6):613-620.
The proinflammatory cytokine interleukin-1 (IL-1) elicits catabolic effects on the myocardial extracellular matrix (ECM) early after myocardial infarction but there is little understanding of its direct effects on cardiac myofibroblasts (CMF), or the role of p38 mitogen-activated protein kinase (MAPK). We used a focused RT-PCR microarray to investigate the effects of IL-1α on expression of 41 ECM genes in CMF cultured from different patients, and explored regulation by p38 MAPK.
IL-1α (10 ng/ml, 6 h) had minimal effect on mRNA expression of structural ECM proteins, including collagens, laminins, fibronectin and vitronectin. However, it induced marked increases in expression of specific ECM proteases, including matrix metalloproteinases MMP-1 (collagenase-1), MMP-3 (stromelysin-1), MMP-9 (gelatinase-B) and MMP-10 (stromelysin-2). Conversely, IL-1α reduced mRNA and protein expression of ADAMTS1, a metalloproteinase that suppresses neovascularization. IL-1α increased expression of TIMP-1 slightly, but not TIMP-2. Data for MMP-1, MMP-2, MMP-3, MMP-9, MMP-10 and ADAMTS1 were confirmed by quantitative real-time RT-PCR. Tumor necrosis factor-alpha (TNFα), another important myocardial proinflammatory cytokine, did not alter expression of these metalloproteinases. IL-1α strongly activated the p38 MAPK pathway in human CMF. Pharmacological inhibitors of p38-α/β (SB203580) or p38-α/β/γ/δ (BIRB-0796) reduced MMP-3 and ADAMTS1 mRNA expression, but neither inhibitor affected MMP-9 levels. MMP-1 and MMP-10 expression were inhibited by BIRB-0796 but not SB203580, suggesting roles for p38-γ/δ.
In summary, IL-1α induces a distinct pattern of ECM protein and protease expression in human CMF, in part regulated by distinct p38 MAPK subtypes, affirming the key role of IL-1α and CMF in post-infarction cardiac remodeling.
doi:10.1016/j.matbio.2010.06.007
PMCID: PMC3004031  PMID: 20619343
ADAMTS, a disintegrin and metalloproteinase domain with thrombospondin motifs; CMF, cardiac myofibroblast; DMSO, dimethylsulfoxide; ECM, extracellular matrix; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HSP27, heat shock protein-27; IL-1, intereukin-1; MAPK, mitogen-activated protein kinase; MI, myocardial infarction; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinases; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; Interleukin-1; Matrix metalloproteinase; Cardiac fibroblast; Extracellular matrix; p38 MAP kinase; Microarray
9.  Flower numbers, pod production, pollen viability, and pistil function are reduced and flower and pod abortion increased in chickpea (Cicer arietinum L.) under terminal drought 
Journal of Experimental Botany  2009;61(2):335-345.
Terminal drought during the reproductive stage is a major constraint to yield of chickpea in many regions of the world. Termination of watering (WS) during podding in a small-seeded desi chickpea (Cicer arietinum L.) cultivar, Rupali, and a large-seeded kabuli chickpea cultivar, Almaz, induced a decrease in predawn leaf water potential (LWP), in the rate of photosynthesis, and in stomatal conductance. Compared to well-watered (WW) controls, the WS treatment reduced flower production by about two-thirds. In the WW treatment, about 15% of the flowers aborted and 42% (Rupali) and 67% (Almaz) of the pods aborted, whereas in the WS treatment 37% and 56% of the flowers aborted and 54% and 73% of the pods aborted, resulting in seed yields of 33% and 15% of the yields in WW plants in Rupali and Almaz, respectively. In vitro pollen viability and germination in Rupali decreased by 50% and 89% in the WS treatment, and pollen germination decreased by 80% in vivo when pollen from a WS plant was placed on a stigma of a WW plant. While about 37% of the germinated pollen tubes from WW plants and 22% from the WS plants reached the ovary in the WW plants, less than 3% of pollen grains reached the ovary when pollen from either WS or WW plants was placed on a stigma of a WS plant. It is concluded that, in addition to pod abortion, flower abortion is an important factor limiting yield in chickpea exposed to terminal drought and that water deficit impaired the function of the pistil/style more than the pollen.
doi:10.1093/jxb/erp307
PMCID: PMC2803204  PMID: 19854801
Flower production; pistil; pod set; pollen; seed yield; stigma; style
10.  Chronic hypoxia inhibits MMP-2 activation and cellular invasion in human cardiac myofibroblasts 
Cardiac myofibroblasts are pivotal to adaptive remodelling after myocardial infarction (MI). These normally quiescent cells invade and proliferate as a wound healing response, facilitated by activation of matrix metalloproteinases, particularly MMP-2. Following MI these reparative events occur under chronically hypoxic conditions yet the mechanisms by which hypoxia might modulate MMP-2 activation and cardiac myofibroblast invasion have not been investigated. Human cardiac myofibroblasts cultured in collagen-supplemented medium were exposed to normoxia (20% O2) or hypoxia (1% O2) for up to 48 h. Secreted levels of total and active MMP-2 were quantified using gelatin zymography, TIMP-2 and membrane-associated MT1-MMP were quantified with ELISA, whole cell MT1-MMP by immunoblotting and immunocytochemistry and MT1-MMP mRNA with real-time RT-PCR. Cellular invasion was assessed in modified Boyden chambers and migration by scratch wound assay.
In the human cardiac myofibroblast, MT1-MMP was central to MMP-2 activation and activated MMP-2 necessary for invasion, confirmed by gene silencing. MMP-2 activation was substantially attenuated by hypoxia (P < 0.001), paralleled by inhibition of myofibroblast invasion (P < 0.05). In contrast, migration was independent of either MT1-MMP or MMP-2. Reduced membrane expression of MT1-MMP (P < 0.05) was responsible for the hypoxic reduction of MMP-2 activation, with no change in either total MMP-2 or TIMP-2. In conclusion, hypoxia reduces MMP-2 activation and subsequent invasion of human cardiac myofibroblasts by reducing membrane expression of MT1-MMP and may delay healing after MI. Regulation of these MMPs remains an attractive target for therapeutic intervention.
doi:10.1016/j.yjmcc.2009.06.002
PMCID: PMC2723933  PMID: 19523958
Collagen; MMP-2; Hypoxia; Invasion; Migration; MT1-MMP
11.  The Reno-Vascular A2B Adenosine Receptor Protects the Kidney from Ischemia 
PLoS Medicine  2008;5(6):e137.
Background
Acute renal failure from ischemia significantly contributes to morbidity and mortality in clinical settings, and strategies to improve renal resistance to ischemia are urgently needed. Here, we identified a novel pathway of renal protection from ischemia using ischemic preconditioning (IP).
Methods and Findings
For this purpose, we utilized a recently developed model of renal ischemia and IP via a hanging weight system that allows repeated and atraumatic occlusion of the renal artery in mice, followed by measurements of specific parameters or renal functions. Studies in gene-targeted mice for each individual adenosine receptor (AR) confirmed renal protection by IP in A1−/−, A2A−/−, or A3AR−/− mice. In contrast, protection from ischemia was abolished in A2BAR−/− mice. This protection was associated with corresponding changes in tissue inflammation and nitric oxide production. In accordance, the A2BAR-antagonist PSB1115 blocked renal protection by IP, while treatment with the selective A2BAR-agonist BAY 60–6583 dramatically improved renal function and histology following ischemia alone. Using an A2BAR-reporter model, we found exclusive expression of A2BARs within the reno-vasculature. Studies using A2BAR bone-marrow chimera conferred kidney protection selectively to renal A2BARs.
Conclusions
These results identify the A2BAR as a novel therapeutic target for providing potent protection from renal ischemia.
Using gene-targeted mice, Holger Eltzschig and colleagues identify the A2B adenosine receptor as a novel therapeutic target for providing protection from renal ischemia.
Editors' Summary
Background.
Throughout life, the kidneys perform the essential task of filtering waste products and excess water from the blood to make urine. Each kidney contains about a million small structures called nephrons, each of which contains a filtration unit consisting of a glomerulus (a small blood vessel) intertwined with a urine-collecting tube called a tubule. If the nephrons stop working for any reason, the rate at which the blood is filtered (the glomerular filtration rate or GFR) decreases and dangerous amounts of waste products such as creatinine build up in the blood. Most kidney diseases destroy the nephrons slowly over years, producing an irreversible condition called chronic renal failure. But the kidneys can also stop working suddenly because of injury or poisoning. One common cause of “acute” renal failure in hospital patients is ischemia—an inadequate blood supply to an organ that results in the death of part of that organ. Heart surgery and other types of surgery in which the blood supply to the kidneys is temporarily disrupted are associated with high rates of acute renal failure.
Why Was This Study Done?
Although the kidneys usually recover from acute failure within a few weeks if the appropriate intensive treatment (for example, dialysis) is provided, acute renal failure after surgery can be fatal. Thus, new strategies to protect the kidneys from ischemia are badly needed. Like other organs, the kidneys can be protected from lethal ischemia by pre-exposure to several short, nonlethal episodes of ischemia. It is not clear how this “ischemic preconditioning” increases renal resistance to ischemia but some data suggest that the protection of tissues from ischemia might involve a signaling molecule called extracellular adenosine. This molecule binds to proteins called receptors on the surface of cells and sends signals into them that change their behavior. There are four different adenosine receptor—A1AR, A2AAR, A2BAR, and A3AR—and in this study, the researchers use ischemic preconditioning as an experimental strategy to investigate which of these receptors protects the kidneys from ischemia in mice, information that might provide clues about how to protect the kidneys from ischemia.
What Did the Researchers Do and Find?
The researchers first asked whether ischemic preconditioning protects the kidneys of mice strains that lack the genes for individual adenosine receptors (A1AR−/−, A2AAR−/−, A2BAR−/−, and A3AR−/− mice) from subsequent ischemia. Using a hanging-weight system, they intermittently blocked the renal artery of these mice before exposing them to a longer period of renal ischemia. Twenty-four hours later, they assessed the renal function of the mice by measuring their blood creatinine levels, GFRs, and urine production. Ischemic preconditioning protected all the mice from ischemia-induced loss of kidney function except the A2BAR−/− mice. It also prevented ischemia-induced structural damage and inflammation in the kidneys of wild-type but not A2BAR−/− mice. These results suggest that A2BAR may help to protect the kidneys from ischemia. Consistent with this idea, ischemic preconditioning did not prevent ischemia-induced renal damage in wild-type mice treated with a compound that specifically blocks the activity of A2BAR. However, wild-type mice (but not A2BAR−/− mice) treated with an A2BAR agonist (which activates the receptor) retained their kidney function after renal ischemia without ischemic preconditioning. Finally, the researchers report that A2BAR has to be present on the blood vessels in the kidney to prevent ischemia-induced acute renal failure.
What Do These Findings Mean?
These findings suggest that the protection of the kidneys from ischemia and the renal resistance to ischemia that is provided by ischemic preconditioning involve adenosine signaling through A2BAR. They also suggest that adenosine might provide protection against ischemia-induced damage by blocking inflammation in the kidney although other possible mechanisms of action need to be investigated. Importantly, these findings suggest that A2BAR might be a therapeutic target for the prevention of renal ischemia. However, results obtained in animals do not always reflect the situation in people, so before A2BAR agonists can be used to reduce the chances of patients developing acute renal failure after surgery, these results need confirming in people and the safety of A2BAR agonists need to be thoroughly investigated.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050137.
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The MedlinePlus encyclopedia has a page on acute kidney failure (in English and Spanish)
Wikipedia has pages on acute renal failure, ischemia, ischemic preconditioning, and adenosine (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050137
PMCID: PMC2504049  PMID: 18578565
12.  Stage-Specific Action of Matrix Metalloproteinases Influences Progressive Hereditary Kidney Disease 
PLoS Medicine  2006;3(4):e100.
Background
Glomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving α3(IV), α4(IV), or α5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood.
Methods and Findings
We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)—MMP-2, MMP-3, and MMP-9—which influence the progression of renal dysfunction in α3(IV) −/− mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the α3(IV) −/− mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of α3(IV) −/− mice.
Conclusions
These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in α3(IV) −/− mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria.
In a mouse model of Alport disease, matrix metalloproteinases appear to have a crucial dual role in disease progression, with an early pathogenic function and a later protective action.
doi:10.1371/journal.pmed.0030100
PMCID: PMC1391977  PMID: 16509766
13.  PLOS Biology 
BMJ : British Medical Journal  2004;328(7430):56.
An open access online journal from the Public Library of Science; first issue October 2003
ISSN 1544 9173 www.plosbiology.org
Rating: ★★★★
PMCID: PMC314264
14.  Personal View 
British Medical Journal  1977;1(6052):44.
PMCID: PMC1603599

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