Polymerization of human angiotensinogen: insights into its structural mechanism and functional significance

Stanley, Peter; Serpell, Louise C.; Stein, Penelope E.

doi:10.1042/bj20060444

Cited by 6 publications

(6 citation statements)

References 52 publications

(75 reference statements)

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“…5D), respectively. Because the molecular mass was much higher than the theoretical mass of the complex, this suggests that these bands contain multimers of miropin that cannot be dissociated by boiling in SDS-PAGE sample buffer as observed previously for other serpins (34). Such dimers/trimers or higher multimers must contain a serpin molecule covalently attached to one end of the protease.…”

Section: Specificity Spectrum and Stoichiometry Of Inhibition Of Protmentioning

confidence: 92%

Miropin, a Novel Bacterial Serpin from the Periodontopathogen Tannerella forsythia, Inhibits a Broad Range of Proteases by Using Different Peptide Bonds within the Reactive Center Loop

Książek

Mizgalska

Enghild

et al. 2015

Journal of Biological Chemistry

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Background: Serpins are uncommon in bacteria; little is known about their function. Results: Serpin from T. forsythia (miropin) inhibits a broad array of proteases with divergent specificities. Conclusion: Miropin may allow T. forsythia to dwell in a highly proteolytic environment. Significance: Miropin is the first pathogen-derived serpin with the unusual ability to efficiently inhibit different proteases at several active sites.

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Section: Specificity Spectrum and Stoichiometry Of Inhibition Of Protmentioning

confidence: 92%

Miropin, a Novel Bacterial Serpin from the Periodontopathogen Tannerella forsythia, Inhibits a Broad Range of Proteases by Using Different Peptide Bonds within the Reactive Center Loop

Książek

Mizgalska

Enghild

et al. 2015

Journal of Biological Chemistry

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“…Likewise, the charge barrier in the GFB and the endothelial glycocalyx are also not likely to be responsible, because both AGT and albumin are negatively charged (more so in albumin). 24,26,27 Polymerization of the injected AGT 28 and/or binding to other plasma proteins could have caused lower glomerular permeability. However, electrophoresis of the infused solution and the animals' sera showed that the size of the majority of labeled proteins was around 60 kD (Supplemental Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Multiphoton Imaging of the Glomerular Permeability of Angiotensinogen

Nakano

Kobori

Burford

et al. 2012

Journal of the American Society of Nephrology

112

118

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Patients and animals with renal injury exhibit increased urinary excretion of angiotensinogen. Although increased tubular synthesis of angiotensinogen contributes to the increased excretion, we do not know to what degree glomerular filtration of systemic angiotensinogen, especially through an abnormal glomerular filtration barrier, contributes to the increase in urinary levels. Here, we used multiphoton microscopy to visualize and quantify the glomerular permeability of angiotensinogen in the intact mouse and rat kidney. In healthy mice and Munich-Wistar-Frömter rats at the early stage of glomerulosclerosis, the glomerular sieving coefficient of systemically infused Atto565-labeled human angiotensinogen (Atto565-hAGT), which rodent renin cannot cleave, was only 25% of the glomerular sieving coefficient of albumin, and its urinary excretion was undetectable. In a more advanced phase of kidney disease, the glomerular permeability of Atto565-hAGT was slightly higher but still very low. Furthermore, unlike urinary albumin, the significantly higher urinary excretion of endogenous rat angiotensinogen did not correlate with either the Atto565-hAGT or Atto565-albumin glomerular sieving coefficients. These results strongly suggest that the vast majority of urinary angiotensinogen originates from the tubules rather than glomerular filtration. The renin-angiotensin system (RAS) is one of the most important regulatory mechanisms of body fluid, electrolyte homeostasis, and BP. 1-4 RAS in the kidney is independently regulated from RAS in the systemic circulation, and it has been implicated in the development of hypertension and kidney diseases. For example, renal epithelial cellspecific overexpression of human angiotensinogen (AGT) in human renin transgenic mice resulted in increased renal angiotensin II, hypertension, and renal fibrosis without any changes in circulating angiotensin II. 5 Also, Dahl salt-sensitive rats, which show low plasma renin activity under high salt feeding, had higher renal angiotensin II content in the kidney compared with normal salt-fed control animals. 6 Although all components that are necessary for angiotensin II production are expressed in the kidney, 3 AGT is, currently, the only component that is noninvasively measurable in the urine of patients. The level of urinary AGT reflects the activity of the intrarenal RAS, and it is associated with pathologic states in several experimental 7,8 and clinical studies. 9,10 Although the major source of the circulating AGT is the liver, we and others have previously shown that AGT is produced in the proximal tubules through a de novo pathway. 3,11

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“…In vitro, the AGT molecule is known to be able to form disulfide-linked multimers, that are suggested to be the dominant constituent of the HMW fraction [16]. In addition, the presence of two different complexes containing proMBP (proform of eosinophil major basic protein) disulfide linked to AGT have been demonstrated [17,18].…”

Section: Introductionmentioning

confidence: 99%

Formation of high-molecular-weight angiotensinogen during pregnancy is a result of competing redox reactions with the proform of eosinophil major basic protein

Kløverpris

Skov

Glerup

et al. 2012

Biochemical Journal

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The plasma concentration of the placentally derived proMBP (proform of eosinophil major basic protein) increases in pregnancy, and three different complexes containing proMBP have been isolated from pregnancy plasma and serum: a 2:2 complex with the metalloproteinase, PAPP-A (pregnancy-associated plasma protein-A), a 2:2 complex with AGT (angiotensinogen) and a 2:2:2 complex with AGT and complement C3dg. In the present study we show that during human pregnancy, all of the circulating proMBP exists in covalent complexes, bound to either PAPP-A or AGT. We also show that the proMBP-AGT complex constitutes the major fraction of circulating HMW (high-molecular weight) AGT in late pregnancy, and that this complex is able to further associate with complement C3 derivatives post-sampling. Clearance experiments in mice suggest that complement C3-based complexes are removed faster from the circulation compared to monomeric AGT and the proMBP-AGT complex. Furthermore, we have used recombinant proteins to analyse the formation of the proMBP-PAPP-A and the proMBP-AGT complexes, and we demonstrate that they are competing reactions, depending on the same cysteine residue of proMBP, but differentially on the redox potential, potentially important for the relative amounts of the complexes in vivo. These findings may be important physiologically, since the biochemical properties of the proteins change as a consequence of complex formation.

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Polymerization of human angiotensinogen: insights into its structural mechanism and functional significance

Cited by 6 publications

References 52 publications

Miropin, a Novel Bacterial Serpin from the Periodontopathogen Tannerella forsythia, Inhibits a Broad Range of Proteases by Using Different Peptide Bonds within the Reactive Center Loop

Miropin, a Novel Bacterial Serpin from the Periodontopathogen Tannerella forsythia, Inhibits a Broad Range of Proteases by Using Different Peptide Bonds within the Reactive Center Loop

Multiphoton Imaging of the Glomerular Permeability of Angiotensinogen

Formation of high-molecular-weight angiotensinogen during pregnancy is a result of competing redox reactions with the proform of eosinophil major basic protein

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