Automated blood pressure readings in primary care demonstrate better correlation to the gold standard of ambulatory monitoring than manual assessment.


Despite the use of gold standard equipment such as mercury sphygmomanometers in primary care for the measurement of blood pressure, accuracy remains a problem. This is due to a combination of system (eg, lack of calibration of instruments), physician (eg, observer error) and patient (eg, sympathetic drive) factors. Programmable automatic and semiautomatic oscillometric devices are likely to replace such devices because of occupational health concerns with the use of mercury.

Methods

This is a cluster randomised controlled study of an automated oscillometric blood pressure device method of determining blood pressure (intervention) versus usual manual measurement (control) in primary care. Both arms ambulatory blood pressure (ABP) measurements were also taken. The study included 555 patients with systolic hypertension (treated and untreated) and no serious comorbidities under the care of 88 primary care physicians in 67 Canadian primary care practices. The intervention was an automated oscillometric blood pressure device (BpTRU) programmed to take six recordings at 2 min intervals. Physicians and practice staff were instructed to observe the first measurement to check whether the device was correctly fitted and then exit the room to minimise white coat effect.

Two outcomes were assessed: the difference in systolic blood pressures (SBPs) between (1) awake ABP minus automated blood pressure measurement and (2) awake ABP minus manual blood pressure measurement. Practices were cluster randomised to intervention or control although the mechanism of randomisation was not specified. Randomisation was stratified by the four cities where the study took place. Neither the timeframe of this study nor the period of follow-up was stated.

Findings

The estimated mean difference for the intervention group between the awake ambulatory SBP/diastolic blood pressure (DBP) and automated clinic blood pressure (−2.3, 95% CI −0.31 to −4.3/−3.3, −2.7 to −4.4) was less (p=0.006/p=0.26) than the difference in the control group between the awake ABP and the manual clinic blood pressure (−6.5, 95% CI −4.3 to −8.6/−4.3, −2.9 to −5.8). Automated clinic SBP/DBP showed a stronger (p<0.001) within group correlation (r=0.34/r=0.56) with awake ABP after enrolment compared with manual clinic blood pressure versus awake ABP before enrolment (r=0.10/r=0.40); the mean difference in r was 0.24 (0.12 to 0.36)/0.16 (0.07 to 0.25). The between-group correlation comparing automated clinic DBP and awake ABP (r=0.56) was stronger (p<0.001) than that for manual clinic blood pressure versus awake ABP (r=0.30); the mean difference in r was 0.26 (0.09 to 0.41). The net reduction in blood pressure that can be attributed specifically to the automated clinic blood pressure intervention was −5.4/−2.1 mm Hg.

Commentary

This study had a high level of physicians consenting to participate (43% of those approached) and providing enough patients (41%). No practice inclusion or exclusion criteria were described. It would seem reasonable that practices should not have oscillometric devices in situ to avoid contamination. Patient eligibility was SBP ≥160 mm Hg and DBP <95 mm Hg (untreated) and SBP ≥140 mm Hg and DBP <90 mm Hg (treated) on last prestudy visit. These criteria seem to have been chosen to allow investigation of the white coat effect. By doing so, however, it has not allowed assessment of effects on reverse white coat or masked hypertension, or differences between the two methods over a broader range of blood pressure measurements.

There were unequal clusters in each arm (36 oscillometric devices and 31 manual devices) and therefore physicians (52 vs 36) and patients (303 vs 252). This was attributed to chance by the authors. It could have been avoided if practices were stratified by number of physicians in the study rather than region. The intervention was described as ‘automated office blood pressure using the BpTRU device’. However, it was more than this, as this arm was also instructed to take multiple measures in an isolated room with the observer absent after the initial measurement. No direct observation seems to have been made for compliance checking purposes.

Implementation of the study findings will be facility dependent. The authors report that, in Canada, primary care physicians generally use several examination rooms. This is likely not to be the case elsewhere, especially, in healthcare systems where primary care is not financially well supported. Our own cluster randomised study has shown that simply replacing the manual machines with oscillometric devices leads to improved blood pressure management.1

The net reduction in blood pressure measurement in the intervention arm versus the control was −5.4/−2.1 mm Hg. This can be seen as validating its correlation with awake ABP measurements, and this is an additional value of the intervention. It may be a surrogate method of establishing measures representative of those made away from the clinic where such facilities are not available to the clinician. In our study of 8529 individuals from 11 hypertension referral centres with a mean clinic SBP/DBP of 142/82 mm Hg, average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ABP.2 This is very similar to the 5/2 mm Hg in this group with an average 141/80 mm Hg in the manual measurement arm.

In summary, this study adds further evidence for the adoption of oscillometric devices in primary healthcare.

Source:Evidence Based Medicine.

 

LHC sees hint of lightweight Higgs boson .


The ultra-shy Higgs boson may have finally shown itself at the LHC. Both of the main detectors, ATLAS and CMS, have uncovered hints of a lightweight Higgs. If it pans out, the only remaining hole in the standard model would be filled.

Even more exciting, a Higgs of this mass, about 125 gigaelectronvolts, would also blast a path to uncharted terrain. Such a featherweight would need at least one new type of particle to stabilise it. “It’s very exciting,” says CMS spokesman Guido Tonelli. “This could be the first ring in a chain of discoveries.”

As the leading theory for how particles and forces interact, the standard model has been spectacularly successful since it was proposed in the 1960s. But it works only on the assumption that the Higgs boson actually exists. The particle is the calling card of an unseen entity called the Higgs field, which is thought to give all particles their mass. The trouble is the standard model cannot predict what the Higgs itself weighs.

So physicists have been hunting for the simplest version of the Higgs at various particle colliders for years. Experiments have steadily ruled it out at a range of masses, except for a narrow window between 115 and 141 GeV.

Now physicists at the Large Hadron Collider at CERN, near Geneva in Switzerland, have probed that range in more detail than ever before. Today, Tonelli and Fabiola Gianotti, head of the ATLAS detector, separately presented results from more than 300 trillion high-speed particle collisions made in the last year. “This is the first time we’re really exploring the entire [mass] region with the right sensitivity – the one that will allow you, if there is something there, to start seeing something,” says Tonelli.

Similar mass

The ATLAS data restricts the Higgs to within 115 and 131 GeV; CMS rules out a Higgs heavier than 127 GeV.

Most excitingly, ATLAS saw a tantalising hint of the Higgs at 126 GeV; CMS saw one at 124 GeV. It is the first time both experiments have seen a signal at nearly the same mass. “We’re very competitive, but once I see they’re coming with results, I’m happy,” Tonelli says. “Their results are important for us. They’re obtained in a completely independent manner.”

The Higgs is expected to appear fleetingly in the wreckage of high-speed proton collisions at the LHC, but cannot be seen directly. Instead physicists look for the shower of lighter particles and photons that result from the decay of Higgs bosons of various masses. Because garden-variety particles also produce the same decay products, Higgs hunters look out for suspicious excesses of these products in their detectors.

Tentative signal

Although both teams see an excess around the same mass, there is not yet enough data to claim a discovery. The ATLAS signal has a statistical significance at 126 GeV of 2.3 sigma, meaning that the result has around a 2 per cent chance of being down to a random fluctuation; the comparable excess at CMS has a significance of just 1.9 sigma. To claim a discovery you need a 5 sigma signal, meaning there is less than 1 in a million chance of the result being a fluke. “There’s clearly not enough to conclude anything at this stage,” Gianotti says. “It could be something interesting, or just a fluctuation.”

Even a hint of a 125-GeV Higgs has some theorists sighing with relief. Although the standard model can’t predict the particle’s mass directly, it does predict how other particles interact with the Higgs – in particular, the W and Z bosons that are responsible for the weak nuclear force.

Earlier experiments found that the W and Z bosons weigh 80.4 and 91.2 GeV, respectively. Because of the way those particles interact, the Higgs mass probably comes out somewhere between about 115 and 130 GeV. A Higgs at 125 GeV or so “is just what the doctor ordered,” says Nobel laureate Frank Wilczek of the Massachusetts Institute of Technology.

New physics

That mass also paves the way for physics beyond the standard model. Thanks to subtle quantum mechanical effects, a lightweight Higgs needs a heavier companion particle “acting as a sort of bodyguard”, Tonelli says. Otherwise, the quantum vacuum from which particles appear would be unstable, and the universe would long ago have disintegrated. If the Higgs is lightweight, the fact that we are here today suggests there is at least one extra particle beyond the standard model.

Wilczek thinks that’s great news. It leaves the door open for one of the most mathematically beautiful extensions of the standard model. Supersymmetry or SUSY for short, suggests that every known particle has an as yet-undetected partner and promises to resolve a lot of the standard model’s shortcomings. It can unite the strong and weak nuclear forces with the electromagnetic force and offers a candidate for dark matter.

The simplest version of the theory predicts that its extra partner particles should already be showing up at the LHC – and they’re not. If the Higgs really weighs about 125 GeV, it could give the ailing theory new life. “In some sense SUSY will receive some oxygen,” Tonelli says. “Maybe not the most trivial and popular models, but there will be a revival of interest in it. SUSY will still be an important area of research for LHC experiments next year.”

First glimpse

In the meantime, ATLAS and CMS physicists will be crunching more data to find out if the hints of a lightweight Higgs hold up. Rigorously combining the two current data sets would effectively double the statistics; Tonelli suspects it would firm up the statistical significance to between 3.7 and 3.9 sigma, or a 1 in 10,000 chance of the result being a fluke.

Assuming the collider keeps working well, both experiments should have enough data to confirm or deny the simplest version of the Higgs by the end of 2012. By then, physicists might look back on this moment as their first glimpse of a major discovery. “This is why there is some excitement,” says Tonneli.

It would also be thrilling if the Higgs never showed up at all. If the current hints disappear, physicists will wait until the LHC revs up to its full energy in 2015 to look for other particles or phenomena that could give particles mass without any need for the Higgs. “There must be something else that plays that role,” Gianotti says. “We will be after that something else.”

Source:New Scientist.

 

 

 

What is the Higgs boson and why does it matter?


If the Higgs is discovered, it will represent perhaps one of the greatest triumphs of the human intellect in recent memory, vindicating the construction of one of science’s greatest theories and the most complicated machine ever built. That’s the good news.

But if the Higgs is all that is found at the Large Hadron Collider (LHC), a huge amount will remain to be discovered. Crucial experimental guidance that physicists need to understand fundamental questions about our existence – from whether all four forces in nature are unified in some grand theory to determining what may have caused the big bang – will still be absent. Answering these questions may be beyond our technical and financial capabilities in this generation.

Now for the long answer:

If our ideas about the Higgs boson turn out to be correct, then everything we see is a kind of window dressing based on an underlying fabric of reality in which we shouldn’t exist. The particles that make us up – which bind together to form protons, neutrons, nuclei and ultimately atoms – have mass. Without the Higgs, these particles would be massless, like photons.

We all know from our own experience that how heavy something feels depends on where it is located. For example, objects that are heavy on land appear lighter in water. Similarly, if you try to push a spoon through treacle it appears heavier than if you push it through air.

The standard model of particle physics implies that there is a “Higgs field” that permeates all space. This field interacts with particles, and does so with varying strengths. Particles that interact more strongly experience more resistance to their motion and appear heavier. Some particles, such as photons, do not interact with the field at all and remain massless.

In this way, the mass of everything is determined by the existence of the field, and mass is an accident of our circumstances because we exist in a universe in which such a background field happens to have arisen.

Playing subatomic catch

But why a Higgs particle? Relativity tells us that no signal can travel faster than light. Incorporating this into quantum mechanics tells us that forces which we think of as being due to fields are actually transmitted between objects by the exchange of particles. The way particles transmit forces is a bit like a game of catch: if I throw a ball and you catch it, I will be pushed backwards by the act of throwing and you will be pushed backwards by the act of catching. Thus we act as if we repel each other.

So if there is a Higgs field, it turns out that there has to be a particle associated with this field, and this is the Higgs particle.

This seems a fanciful framework, rather like imagining angels on the head of a pin. What would drive scientists to imagine such a scenario? One of the greatest successes of the past 50 years was the unification of two of the forces of nature: electromagnetism and the weak interaction. In this “electroweak” theory, electromagnetic forces arise by the long-range exchange of massless photons, and the short-range weak force is due to the exchange of massive particles called W and Z particles, predicted in the 1960s and discovered in the 1980s at CERN, the European particle physics laboratory near Geneva, Switzerland, which is now the home of the LHC.

In order for this theoretical unification to make mathematical sense, all three particles have to be massless in the underlying theory, and therefore the forces they mediate would be almost identical. Only if the W and Z particles obtain a mass by interacting with a background field – the Higgs field – will the underlying unified theory explain why the two forces appear different at the scales we measure them today, while remaining mathematically consistent.

High mass

Theory suggests that the mass of a Higgs particle should be about 100 times the mass of the proton; however, the exact mass is not predicted.

For over 25 years since the discovery of the W and Z particles, experimental physicists have been trying to build particle accelerators with the energy necessary to produce a Higgs particle, if it exists. The Tevatron accelerator at Fermilab in Batavia, Illinois, was able to reach up to about 120 times the mass of the proton (about 120 gigaelectronvolts) but did not find the Higgs.

The LHC was designed to probe for Higgs masses heavier than this. If the Higgs particle is announced with a mass of 125 GeV, as the rumours suggest, it will be the crown jewel of our theoretical understanding of the electroweak unified theory, our own origins and the origin of almost all mass we measure in the universe.

All is not that rosy, however. The standard model gives no explanation of the masses of the Higgs, the W and Z. Indeed, other arguments suggest that we need new physics to explain why quantum mechanical effects should not make this scale of masses is not much higher.

One of the most exciting ways in which this behaviour might be kept in check involves a theory called supersymmetry. If supersymmetry is real, the number of elementary particles would double, and we would need not one Higgs particle but two. This is what many physicists have expected to find. The rumours from CERN suggest a second particle at about 140 GeV.

Since supersymmetry is an essential ingredient of the more speculative string-theory models that attempt to unify gravity and quantum mechanics, there is even more reason for some theorists to hope that either two Higgs particles, or even unsuspected particles, might be discovered.

If a single Higgs and nothing else is discovered at the LHC it will therefore be a mixed blessing – perhaps the worst possibility we theorists can imagine. We will have discovered the origin of mass, as advertised, but there will be no new experimental guidance on how to take the next step.

Source:New Scientist.

 

 

 

Neutrinos may be tachyons


For a few days in September 2011, it was the biggest story in the world. The little-known OPERA experiment in Gran Sasso, Italy, had just made an electrifying claim – that subatomic particles called neutrinos had travelled faster than the speed of light. Next year, two experiments – MINOS at Fermilab in Batavia, Illinois, and T2K in Japan (pictured) – will be able to test the claim. If it stands up, how should we meld these misbehaving particles with the rest of physics?

One option is via tachyons, hypothetical particles that are born speeding faster than light. It turns out that the speed limit imposed by Einstein’s special theory of relativity isn’t so much a cap that nothing can exceed as a barrier that nothing can cross. Tachyons were dreamed up to illustrate this: particles born faster than light pose no problem for special relativity as long as they spend their whole lives in the fast lane.

Are neutrinos tachyons? One way they might be is if the universe is filled with a field that interacts with particles as they fly through it. If photons have more drag in that field than neutrinos do, then neutrinos would naturally outpace the speed of light. This idea may feel familiar: light travels slower in glass than in a vacuum, for instance. So the universe might be permeated with a sort of diffuse glass.

If neutrinos do turn out to be tachyons, theorists will still have their work cut out. Though they are born speeding, tachyons interfere with another demand of special relativity: that a particle’s behaviour be the same no matter where it is facing or how fast it is going. Meanwhile, there is no shortage of other theories scrabbling to explain this most astonishing of results.

source:New scientist.

 

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats.


Hepatic fibrosis, the major complication of virtually all types of chronic liver damage, usually begins in portal areas, and its severity has been correlated to liver progenitor cells (LPC) expansion from periportal areas, even if the primary targets of injury are intralobular hepatocytes. The aim of this study was to determine the potential fibrogenic role of LPC, using a new experimental model in which rat liver fibrosis was induced by chronic carbon tetrachloride (CCl4) administration for 6 weeks, in combination with chronic acetylaminofluorene treatment (AAF), which promotes activation of LPC compartment. Treatment with CCl4 alone caused a significant increase in serum transaminase activity as well as liver fibrosis initiating around central veins and leading to formation of incomplete centro-central septa with sparse fibrogenic cells expressing α-smooth muscle actin (αSMA). In AAF/CCl4-treated animals, the fibrogenic response was profoundly worsened, with formation of multiple porto-central bridging septa leading to cirrhosis, whereas hepatocellular necrosis and inflammation were similar to those observed in CCl4-treated animals. Enhanced fibrosis in AAF/CCl4 group was accompanied by ductule forming LPC expanding from portal areas, αSMA-positive cells accumulation in the fibrotic areas and increased expression of hepatic collagen type 1, 3 and 4 mRNA. Moreover, CK19-positive LPC expressed the most potent fibrogenic cytokine transforming growth factor-β (TGFβ) without any expression of αSMA, desmin or fibroblast-specific protein-1, demonstrating that LPC did not undergo an epithelial–mesenchymal transition. In this new experimental model, LPC, by expressing TGFβ, contributed to the accumulation of αSMA-positive myofibroblasts in the ductular reaction leading to enhanced fibrosis but also to disease progression and to a fibrotic pattern similar to that observed in humans.

Source:Nature Pathology.


 

 

Bevacizumab + chemoradiation improves survival in nasopharyngeal carcinoma.


Researchers at Memorial Sloan-Kettering Cancer Center have reported that the addition of bevacizumab to concurrent and adjuvant chemoradiation with cisplatin and fluorouracil improved survival in 44 patients from 19 centers in North American and Hong Kong with untreated stage IIB-IVB nasopharyngeal carcinoma. There were no patients with grade 3-4 hemorrhage and no grade 5 adverse events. With a mean follow-up of 2.5 y, the 2-y locoregional PFS was 83.7%, the 2-y distant metastatis-free survival was 90.8%, the 2-y PFS was 74.7%, and the OS was 90.9%.

Source:MSKCC

 

Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial


 Background

We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy.

Methods

We enrolled patients older than 18 years with stage IIB—IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m2) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m2), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m2 per day), given on days 64—67, 85—88, and 106—109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694.

Findings

From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3—4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1—2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3—4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2·5 years (IQR 2·1—2·9), the estimated 2 year locoregional progression-free interval was 83·7% (95% CI 72·6—94·9), the 2 year distant metastasis-free interval was 90·8% (82·2—99·5), the 2 year progression-free survival was 74·7% (61·8—87·6), and 2 year overall survival was 90·9% (82·3—99·4).

Interpretation

The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease.

Funding

National Cancer Institute, USA.

Source:Lancet Oncology

Fascin, a novel marker of human hepatic stellate cells, may regulate their proliferation, migration, and collagen gene expression through the FAK-PI3K-Akt pathway.


Fascin is a component of actin bundles and may regulate various cellular events. The expression and function of fascin in human hepatic stellate cells (HSCs) has remained largely uncharacterized. Fascin expression in human liver tissue was studied using immunohistochemistry. To identify cells expressing fascin, double immunofluorescent staining with vimentin, α-smooth muscle actin (α-SMA), or fibulin-2 was performed and analyzed with confocal microscopy. In culture experiments, fascin expression and the phosphorylation of focal adhesion kinase (FAK) and Akt in LX-2 cells, a cell line of human HSCs, were investigated using western blot. Specific siRNAs were used to reduce the expression of fascin in LX-2 cells. Proliferation and migration were assayed with a CyQuant assay kit and a Matrigel-coated culture insert system, respectively. Levels of matrix metalloproteinase (MMP)-2 and collagen mRNAs were examined using quantitative RT-PCR. Immunohistochemistry revealed the expression of fascin along sinusoids and overlapping with vimentin and α-SMA in both non-fibrotic and fibrotic liver tissue, but it was almost absent in periportal myofibroblastic cells and did not colocalize with fibulin-2, a marker of portal myofibroblasts. In addition, fascin immunoreactivity was almost undetectable in septa of fibrotic human liver tissue. The expression of fascin in LX-2 cells was confirmed using western blot. Two different specific siRNAs against fascin significantly reduced the number of viable LX-2 cells to 65% compared with control cultures and downregulated the mRNAs levels of types I and III collagen and MMP-2 to 62%, 65%, and 70% of control levels, respectively. This condition also reduced the migration activity of LX-2 cells to 46% of control cells and the phosphorylation level of both FAK and Akt. Fascin may be an excellent novel marker of human HSCs that distinguishes HSCs from periportal myofibroblasts. Fascin may regulate functions of human HSCs through the FAK-phosphoinositide 3-kinase-Akt pathway.

Source:Nature Oncology

 

Microvascular density as an independent predictor of clinical outcome in renal cell carcinoma: an automated image analysis study.


Tumor microvascular density (MVD) has been shown to correlate with the aggressiveness of several cancers. With the introduction of targeted anti-angiogenic therapy, assessment of MVD has the potential not only as a prognostic but also as a therapeutic marker. The significance of tumor vascularity in clear cell renal cell carcinoma (ccRCC) has been debated, with studies showing contradictory results. Previous studies were limited by manual quantification of MVD within a small area of tumor. Since then, the validity of this method has been questioned. To avoid the inaccuracies of manual quantification, we employed a computerized image analysis, which allowed assessment of large areas of tumor and adjacent normal tissue. The latter was used as an internal reference for normalization. MVD and vascular endothelial growth factor (VEGF) were assessed in 57 cases of ccRCC. Sections were immunostained for CD34 and VEGF. Areas of ccRCC and normal kidney medulla were analyzed within scanned images using software that counted CD34-positive vessels and measured the intensity of VEGF staining. We obtained unadjusted values from tumoral areas and calculated adjusted values as tumor/normal ratios. Unadjusted MVD had no association with clinical outcome. However, similarly to tumor stage, higher adjusted MVD was associated with shorter disease-free survival (log-rank P=0.037, Cox P=0.02). This was significant in univariate and multivariate analyses. MVD did not correlate with tumor stage, pointing to its independent prognostic value. As expected due to the known molecular abnormalities in ccRCC, most tumors showed higher VEGF expression than normal tissue. Higher adjusted VEGF was associated with high tumor grade (P=0.049). The finding of increased MVD as an independent marker of tumor aggressiveness may prove useful in the development of new tests for prognostic and therapeutic guidance. Digital techniques can provide more accurate assessment of immunomarkers and may reveal less obvious associations.

Source:Nature Pathology.

 

 

HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II


Apoptosis is a driving force of diabetic end-organ damage, including diabetic nephropathy (DN). However, the mechanisms that modulate diabetes-induced cell death are not fully understood. Heat shock protein 27 (HSP27/HSPB1) is a cell stress protein that regulates apoptosis in extrarenal cells and is expressed by podocytes exposed to toxins causing nephrotic syndrome. We investigated the regulation of HSPB1 expression and its function in podocytes exposed to factors contributing to DN, such as high glucose and angiotensin (Ang) II. HSPB1 expression was assessed in renal biopsies from patients with DN, minimal change disease or focal segmental glomerulosclerosis (FSGS), in a rat model of diabetes induced by streptozotocin (STZ) and in Ang II-infused rats. The regulation of HSPB1 was studied in cultured human podocytes and the function of HSPB1 expressed in response to pathophysiologically relevant stimuli was explored by short interfering RNA knockdown. Total kidney HSPB1 mRNA and protein expression was increased in rats with STZ-induced diabetes and in rats infused with Ang II. Upregulation of HSPB1 protein was confirmed in isolated diabetic glomeruli. Immunohistochemistry showed increased glomerular expression of HSPB1 in both models and localized glomerular HSPB1 to podocytes. HSPB1 protein was increased in glomerular podocytes from patients with DN or FSGS. In cultured human podocytes HSPB1 mRNA and protein expression was upregulated by high glucose concentrations and Ang II. High glucose, but not Ang II, promoted podocyte apoptosis. HSPB1 short interfering RNA (siRNA) targeting increased apoptosis in a high-glucose milieu and sensitized to Ang II or TGFβ1-induced apoptosis by promoting caspase activation. In conclusion, both high glucose and Ang II contribute to HSPB1 upregulation. HSPB1 upregulation allows podocytes to better withstand an adverse high-glucose or Ang II-rich environment, such as can be found in DN.

Source:Nature Pathology.