Renal cathepsin G and angiotensin II generation

Rykl, Jana; Thiemann, Joachim; Kurzawski, Sandra; Pohl, Thomas; Gobom, Johan; Zidek, Walter; Schlüter, Hartmut

doi:10.1097/01.hjh.0000242404.91332.be

Cited by 42 publications

(32 citation statements)

References 38 publications

(38 reference statements)

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“…Alternatively, reabsorbed Agt may be transferred back to the tubular lumen and then converted to AII, or it may be processed to AII by lysosomal enzymes. 29 The present study does not determine how much of the renal AII is attributed to the Agt reabsorbed by proximal tubule cells as its precursor. To address this quantitative issue, mutant mice with 100% of proximal tubular cells carrying megalin null mutation need to be generated in view of our observation that, in mosaic megalin KOs, Agt protein incorporation of megalin gene intact cells becomes upregulated in a compensatory manner (Supplemental Figure 7).…”

Section: Discussionmentioning

confidence: 81%

Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II

Matsusaka

Niimura

Shimizu

et al. 2012

Journal of the American Society of Nephrology

231

296

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Angiotensin II content in the kidney is much higher than in the plasma, and it increases more in kidney diseases through an uncertain mechanism. Because the kidney abundantly expresses angiotensinogen mRNA, transcriptional dysregulation of angiotensinogen within the kidney is one potential cause of increased renal angiotensin II in the setting of disease. Here, we observed that kidney-specific angiotensinogen knockout mice had levels of renal angiotensinogen protein and angiotensin II that were similar to those levels of control mice. In contrast, liver-specific knockout of angiotensinogen nearly abolished plasma and renal angiotensinogen protein and renal tissue angiotensin II. Immunohistochemical analysis in mosaic proximal tubules of megalin knockout mice revealed that angiotensinogen protein was incorporated selectively in megalin-intact cells of the proximal tubule, indicating that the proximal tubule reabsorbs filtered angiotensinogen through megalin. Disruption of the filtration barrier in a transgenic mouse model of podocyte-selective injury increased renal angiotensin II content and markedly increased both tubular and urinary angiotensinogen protein without an increase in renal renin activity, supporting the dependency of renal angiotensin II generation on filtered angiotensinogen. Taken together, these data suggest that liverderived angiotensinogen is the primary source of renal angiotensinogen protein and angiotensin II. Furthermore, an abnormal increase in the permeability of the glomerular capillary wall to angiotensinogen, which characterizes proteinuric kidney diseases, enhances the synthesis of renal angiotensin II. CKDs are often progressive and involve cardiovascular diseases. Pharmacological intervention of angiotensin II (AII) is the only currently available therapeutic clinical measure with proven effectiveness in protecting the kidney from progressive loss of renal function in CKD. However, in these conditions, circulating AII is typically not elevated. Of note, AII content in renal tissues is markedly higher than content in the circulation, and it is regulated in a manner distinct from circulating AII. 1-3 These findings have formed the currently prevailing notion that the kidney in and of itself is furnished with a full set of components necessary for de novo AII synthesis. In support of this notion, studies have shown that renal AII is elevated in hypertension and

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Section: Discussionmentioning

confidence: 81%

Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II

Matsusaka

Niimura

Shimizu

et al. 2012

Journal of the American Society of Nephrology

231

296

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“…Already, there is ample evidence that such approaches can shed new light into even well studied subject areas such as the renin-angiotensin-system. Using MALDI-MES, Schlüter et al determined that renal Cathepsin G can generate angiotensin II 71 . Using the PALeO-assay, we demonstrated that endothelin-converting enzyme-1 (ECE-1), a member of the neprilysin protease family, can also generate angiotensin II (Figure 3) (M. Hardt, unpublished data, 2011).…”

Section: How To Gain Insights Into the Dynamics Of Proteolytic Procesmentioning

confidence: 99%

Targeting Proteases in Cardiovascular Diseases by Mass Spectrometry-Based Proteomics

Klingler

Hardt

2012

Circ Cardiovasc Genet

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Proteases hydrolyze peptide bonds, thereby controlling the function of proteins and peptides on the posttranslational level. In the cardiovascular system, proteases play pivotal roles in the regulation of blood pressure, coagulation and other essential physiological processes. Accordingly, proteases are prime targets for therapeutic interventions and diagnostics. Proteases are part of complex proteolytic networks comprised of enzymes, inhibitors, activators, substrates and cleavage products. Analyzing these networks on a system-wide level is essential to understanding cardiovascular function and how dysregulation can lead to pathological conditions. Mass spectrometry-based quantitative and dynamic proteomics approaches are leading the way to enhance our knowledge of proteolytic networks such as the renin-angiotensin-system. Here, we critically review proteomics tools utilized in protease biology and provide an overview on how these methods can be used to characterize and validate protease function.

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“…We have recently identified the presence of cathepsin B, a lysosomal cysteine protease that catalyses the conversion of pro-renin into active rennin (27, 28), cathepsin D, an aspartic lysosomal protease bearing significant homology to renin thus engages in renin-like actions of converting AGN to ATI (29, 30), and cathepsin G, a serine protease with the capacity to generate ATII from ATI and directly from AGN (31, 33), within proliferating infantile hemangioma (IH) (34). These cathepsin isozymes catalyze the production of angiotensin peptides without involvement of classical RAS cascade mechanisms and offer a potential explanation for the variable response of IH to treatment using RAS modulators such as β-blockers and ACE inhibitors (31). …”

Section: Introductionmentioning

confidence: 99%

Expression of Cathepsins B, D, and G in Isocitrate Dehydrogenase-Wildtype Glioblastoma

et al. 2017

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AimTo investigate the expression of cathepsins B, D, and G, in relation to the cancer stem cell (CSC) subpopulations, we have previously characterized within isocitrate dehydogenase (IDH)-wildtype glioblastoma (IDHWGB).Methods3,3-Diaminobezidine (DAB) immunohistochemical (IHC) staining for cathepsins B, D, and G, was performed on 4μm-thick formalin-fixed paraffin-embedded IDHWGB samples obtained from six patients. Two representative DHWGB samples from the original cohort of patients were selected for immunofluorescent (IF) IHC staining, to identify the localization of the cathepsins in relation to the CSC subpopulations. NanoString gene expression analysis and colorimetric in situ hybridization (CISH) were conducted to investigate the transcriptional activation of genes encoding for cathepsins B, D, and G. Data obtained from cell counting of DAB IHC-stained slides and from NanoString analysis were subjected to statistical analyses to determine significance.ResultsCathepsin B and cathepsin D were detected in IDHWGB by DAB IHC staining. IF IHC staining demonstrated the expression of both cathepsin B and cathepsin D by the OCT4+ and SALL4+ CSC subpopulations. NanoString gene analysis and CISH confirmed the abundant transcript expression of these cathepsins. The transcriptional and translational expressions of cathepsin G were minimal and were confined to cells within the microvasculature.ConclusionThis study demonstrated the expression of cathepsin B and cathepsin D but not cathepsin G within the CSC subpopulations of IDHWGB at both the transcriptional and translational level. Cathepsin G was expressed at low levels and was not localized to the CSC population of IDHWGB. The novel finding of cathepsin B and cathepsin D in IDHWGB suggests the presence of bypass loops for the renin-angiotensin system, which may facilitate the production of angiotensin peptides. Elucidating the precise role of these cathepsins may lead to better understanding and more effective treatment of this aggressive tumor.

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Renal cathepsin G and angiotensin II generation

Abstract: This is the first time that cathepsin G has been identified in mammalian renal tissue.

Cited by 42 publications

References 38 publications

Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II

Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II

Targeting Proteases in Cardiovascular Diseases by Mass Spectrometry-Based Proteomics

Expression of Cathepsins B, D, and G in Isocitrate Dehydrogenase-Wildtype Glioblastoma

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