3 research outputs found
Podocytes Produce and Secrete Functional Complement C3 and Complement Factor H
Podocytes are an important part of the glomerular filtration barrier and the key player in the development of proteinuria, which is an early feature of complement mediated renal diseases. Complement factors are mainly liver-born and present in circulation. Nevertheless, there is a growing body of evidence for additional sites of complement protein synthesis, including various cell types in the kidney. We hypothesized that podocytes are able to produce complement components and contribute to the local balance of complement activation and regulation. To investigate the relevant balance between inhibiting and activating sides, our studies focused on complement factor H (CFH), an important complement regulator, and on C3, the early key component for complement activation. We characterized human cultured podocytes for the expression and secretion of activating and regulating complement factors, and analyzed the secretion pathway and functional activity. We studied glomerular CFH and C3 expression in puromycin aminonucleoside (PAN) -treated rats, a model for proteinuria, and the physiological mRNA-expression of both factors in murine kidneys. We found, that C3 and CFH were expressed in cultured podocytes and expression levels differed from those in cultivated glomerular endothelial cells. The process of secretion in podocytes was stimulated with interferon gamma and located in the Golgi apparatus. Cultured podocytes could initiate the complement cascade by the splitting of C3, which can be shown by the generation of C3a, a functional C3 split product. C3 contributed to external complement activation. Podocyte-secreted CFH, in conjunction with factor I, was able to split C3b. Podocytes derived from a patient with a CFH mutation displayed impaired cell surface complement regulation. CFH and C3 were synthesized in podocytes of healthy C57Bl/6-mice and were upregulated in podocytes of PAN treated rats. These data show that podocytes produce functionally active complement components, and could therefore influence the local glomerular complement activation and regulation. This modulating effect should therefore be considered in all diseases where glomerular complement activation occurs. Furthermore, our data indicate a potential novel role of podocytes in the innate immune system
Jet energy measurement with the ATLAS detector in proton-proton collisions at = 7 TeV
The jet energy scale (JES) and its systematic uncertainty are determined for
jets measured with the ATLAS detector at the LHC in proton-proton collision
data at a centre-of-mass energy of sqrt(s) = 7 TeV corresponding to an
integrated luminosity of 38 inverse pb. Jets are reconstructed with the anti-kt
algorithm with distance parameters R=0.4 or R=0.6. Jet energy and angle
corrections are determined from Monte Carlo simulations to calibrate jets with
transverse momenta pt > 20 GeV and pseudorapidities eta<4.5. The JES systematic
uncertainty is estimated using the single isolated hadron response measured in
situ and in test-beams. The JES uncertainty is less than 2.5% in the central
calorimeter region (eta<0.8) for jets with 60 < pt < 800 GeV, and is maximally
14% for pt < 30 GeV in the most forward region 3.2<eta<4.5. The uncertainty for
additional energy from multiple proton-proton collisions in the same bunch
crossing is less than 1.5% per additional collision for jets with pt > 50 GeV
after a dedicated correction for this effect. The JES is validated for jet
transverse momenta up to 1 TeV to the level of a few percent using several in
situ techniques by comparing a well-known reference such as the recoiling
photon pt, the sum of the transverse momenta of tracks associated to the jet,
or a system of low-pt jets recoiling against a high-pt jet. More sophisticated
jet calibration schemes are presented based on calorimeter cell energy density
weighting or hadronic properties of jets, providing an improved jet energy
resolution and a reduced flavour dependence of the jet response. The JES
systematic uncertainty determined from a combination of in situ techniques are
consistent with the one derived from single hadron response measurements over a
wide kinematic range. The nominal corrections and uncertainties are derived for
isolated jets in an inclusive sample of high-pt jets.Comment: 100 pages plus author list (111 pages total), 93 figures, 17 tables,
submitted to European Physical Journal