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Article ; Online: Cross talk between the Crumbs complex and Hippo signaling in renal epithelial cells.

Michgehl, U / Pavenstädt, H / Vollenbröker, B

Pflugers Archiv : European journal of physiology

2017 Volume 469, Issue 7-8, Page(s) 917–926

Abstract: Cell polarity has a crucial role in organizing cells into tissues and in mediating transport processes and cell-cell communication. Especially the cells of the nephron require apicobasal polarity to establish and maintain their barrier function. The ... ...

Abstract	Cell polarity has a crucial role in organizing cells into tissues and in mediating transport processes and cell-cell communication. Especially the cells of the nephron require apicobasal polarity to establish and maintain their barrier function. The Crumbs complex including the integral membrane protein Crumbs, as well as Pals1 and Patj, is essential for the establishment of apicobasal polarity. The interactions of the core proteins and the interplay with other processes have been characterized in various epithelial cell lines in detail. Notably, Crb2 and Crb3 are expressed within the kidney and play an important role in the proper function of podocytes and tubules, respectively. The interaction of polarity proteins and components of the Hippo pathway-an evolutionarily highly conserved kinase cascade regulating cell proliferation, organ size, and tissue regeneration-has been discovered recently. Here, we discuss potential molecular and physiological links between the Crumbs complex and the Hippo pathway in renal cells.
Language	English
Publishing date	2017-08
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-017-2004-0
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Article ; Online: Importance of ACE2 for SARS-CoV-2 Infection of Kidney Cells.

Kroll, Marie-Kristin / Schloer, Sebastian / Candan, Peynaz / Korthals, Nadia / Wenzel, Christoph / Ihle, Hannah / Gilhaus, Kevin / Liedtke, Kim Rouven / Schöfbänker, Michael / Surmann, Beate / Schröter, Rita / Neugebauer, Ute / Mall, Gita / Oswald, Stefan / Ludwig, Stephan / Rescher, Ursula / Vollenbröker, Beate / Ciarimboli, Giuliano

Biomolecules

2023 Volume 13, Issue 3

Abstract: In late 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the causative agent of coronavirus disease 2019 (COVID-19) emerged in China and spread rapidly around the world, causing an ongoing pandemic of global concern. COVID- ... ...

Abstract	In late 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the causative agent of coronavirus disease 2019 (COVID-19) emerged in China and spread rapidly around the world, causing an ongoing pandemic of global concern. COVID-19 proceeds with moderate symptoms in most patients, whereas others experience serious respiratory illness that requires intensive care treatment and may end in death. The severity of COVID-19 is linked to several risk factors including male sex, comorbidities, and advanced age. Apart from respiratory complications, further impairments by COVID-19 affecting other tissues of the human body are observed. In this respect, the human kidney is one of the most frequently affected extrapulmonary organs and acute kidney injury (AKI) is known as a direct or indirect complication of SARS-CoV-2 infection. The aim of this work was to investigate the importance of the protein angiotensin-converting enzyme 2 (ACE2) for a possible cell entry of SARS-CoV-2 into human kidney cells. First, the expression of the cellular receptor ACE2 was demonstrated to be decisive for viral SARS-CoV-2 cell entry in human AB8 podocytes, whereas the presence of the transmembrane protease serine 2 (TMPRSS2) was dispensable. Moreover, the ACE2 protein amount was well detectable by mass spectrometry analysis in human kidneys, while TMPRSS2 could be detected only in a few samples. Additionally, a negative correlation of the ACE2 protein abundance to male sex and elderly aged females in human kidney tissues was demonstrated in this work. Last, the possibility of a direct infection of kidney tubular renal structures by SARS-CoV-2 was demonstrated.
MeSH term(s)	Aged ; Female ; Humans ; Male ; Angiotensin-Converting Enzyme 2 ; COVID-19 ; Kidney/metabolism ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; SARS-CoV-2/metabolism
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23)
Language	English
Publishing date	2023-03-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13030472
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Article ; Online: Disruption of the Rab7-Dependent Final Common Pathway of Endosomal and Autophagic Processing Results in a Severe Podocytopathy.

Journal of the American Society of Nephrology : JASN

2023 Volume 34, Issue 7, Page(s) 1191–1206

Abstract: Significance statement: Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates and complex morphology, such as podocytes. To improve ... ...

Abstract	Significance statement: Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates and complex morphology, such as podocytes. To improve our understanding on how disturbances of these trafficking pathways are linked to podocyte depletion and slit diaphragm (SD) injury, the authors explored the role of the small GTPase Rab7, which is linked to endosomal, lysosomal, and autophagic pathways, using as model systems mice and Drosophila with podocyte-specific or nephrocyte-specific loss of Rab7, and a human podocyte cell line depleted for Rab7. Their findings point to maturation and fusion events during endolysosomal and autophagic maturation as key processes for podocyte homeostasis and function and identify altered lysosomal pH values as a putative novel mechanism for podocytopathies. Background: Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates, such as podocytes. How disturbances within these trafficking pathways may act as factors in proteinuric glomerular diseases is poorly understood. Methods: To explore how disturbances in trafficking pathways may act as factors in proteinuric glomerular diseases, we focused on Rab7, a highly conserved GTPase that controls the homeostasis of late endolysosomal and autophagic processes. We generated mouse and Drosophila in vivo models lacking Rab7 exclusively in podocytes or nephrocytes, and performed histologic and ultrastructural analyses. To further investigate Rab7 function on lysosomal and autophagic structures, we used immortalized human cell lines depleted for Rab7. Results: Depletion of Rab7 in mice, Drosophila , and immortalized human cell lines resulted in an accumulation of diverse vesicular structures resembling multivesicular bodies, autophagosomes, and autoendolysosomes. Mice lacking Rab7 developed a severe and lethal renal phenotype with early-onset proteinuria and global or focal segmental glomerulosclerosis, accompanied by an altered distribution of slit diaphragm proteins. Remarkably, structures resembling multivesicular bodies began forming within 2 weeks after birth, prior to the glomerular injuries. In Drosophila nephrocytes, Rab7 knockdown resulted in the accumulation of vesicles and reduced slit diaphragms. In vitro , Rab7 knockout led to similar enlarged vesicles and altered lysosomal pH values, accompanied by an accumulation of lysosomal marker proteins. Conclusions: Disruption within the final common pathway of endocytic and autophagic processes may be a novel and insufficiently understood mechanism regulating podocyte health and disease.
MeSH term(s)	Animals ; Mice ; Humans ; Kidney Glomerulus/pathology ; Podocytes/metabolism ; Endosomes ; Drosophila ; Kidney ; Mammals
Language	English
Publishing date	2023-04-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.0000000000000126
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Article ; Online: Nuclear YAP localization as a key regulator of podocyte function.

Bonse, Jakob / Wennmann, Dirk Oliver / Kremerskothen, Joachim / Weide, Thomas / Michgehl, Ulf / Pavenstädt, Hermann / Vollenbröker, Beate

Cell death & disease

2018 Volume 9, Issue 9, Page(s) 850

Abstract: Podocytes are crucial for the establishment of the blood-urine filtration barrier in the glomeruli of the kidney. These cells are mainly affected during glomerulopathies causing proteinuria and kidney function impairment. Ongoing podocyte injury leads to ...

Abstract	Podocytes are crucial for the establishment of the blood-urine filtration barrier in the glomeruli of the kidney. These cells are mainly affected during glomerulopathies causing proteinuria and kidney function impairment. Ongoing podocyte injury leads to podocyte loss, finally followed by end-stage kidney disease. Podocytes display a predominant nuclear localization of YAP (Yes-associated protein), one effector protein of the Hippo pathway, which regulates the balance between proliferation, differentiation, and apoptosis in cells. Nuclear active YAP seems to be critical for podocyte survival in vivo and in vitro. We can show here that different treatments leading to sequestration of YAP into the cytoplasm in podocytes, like decreased rigidity of the substrate, incubation with dasatinib, or overexpression of Hippo pathway members result in the induction of apoptosis. A RNA sequencing analysis of large tumor suppressor kinase 2 (LATS2) overexpressing podocytes confirmed a significant upregulation of apoptotic genes. The downregulation of Hippo pathway components suggests a feedback mechanism in podocytes. Noteworthy was the regulation of genes involved in cell-cell junction, the composition of the extracellular space, and cell migration. This suggests an influence of Hippo pathway activity on podocyte integrity. As focal segmental glomerulopathy (FSGS) goes along with an activation of the Hippo pathway in podocytes, a comparison of our data with two independent studies of transcriptional regulation in human FSGS glomeruli obtained from the Nephroseq database was performed. This comparison affirmed a multitude of consistent transcriptional changes concerning the regulation of genes influencing apoptosis and the Hippo signaling pathway as well as cell junction formation and cell migration. The link between Hippo pathway activation in podocytes and the regulation of junction and migration processes in vivo might be a fundamental mechanism of glomerular sclerosis and loss of renal function.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Apoptosis/physiology ; Cell Line ; Cell Movement/physiology ; Cell Nucleus/metabolism ; Gene Expression Regulation/physiology ; HEK293 Cells ; Humans ; Kidney/metabolism ; Phosphoproteins/metabolism ; Podocytes/metabolism ; Protein Transport/physiology ; Renal Insufficiency/metabolism ; Signal Transduction/physiology ; Transcription Factors ; Transcription, Genetic/physiology ; Tumor Suppressor Proteins/metabolism ; Up-Regulation/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Phosphoproteins ; Transcription Factors ; Tumor Suppressor Proteins ; YAP1 protein, human
Language	English
Publishing date	2018-08-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-018-0878-1
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Article ; Online: LIM and SH3 protein 1 (LASP-1): A novel link between the slit membrane and actin cytoskeleton dynamics in podocytes.

Lepa, Carolin / Möller-Kerutt, Annika / Stölting, Miriam / Picciotto, Cara / Eddy, Mee-Ling / Butt, Elke / Kerjaschki, Dontscho / Korb-Pap, Adelheid / Vollenbröker, Beate / Weide, Thomas / George, Britta / Kremerskothen, Joachim / Pavenstädt, Hermann

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2020 Volume 34, Issue 4, Page(s) 5453–5464

Abstract: The foot processes of podocytes exhibit a dynamic actin cytoskeleton, which maintains their complex cell structure and antagonizes the elastic forces of the glomerular capillary. Interdigitating secondary foot processes form a highly selective filter for ...

Abstract	The foot processes of podocytes exhibit a dynamic actin cytoskeleton, which maintains their complex cell structure and antagonizes the elastic forces of the glomerular capillary. Interdigitating secondary foot processes form a highly selective filter for proteins in the kidney, the slit membrane. Knockdown of slit membrane components such as Nephrin or Neph1 and cytoskeletal adaptor proteins such as CD2AP in mice leads to breakdown of the filtration barrier with foot process effacement, proteinuria, and early death of the mice. Less is known about the crosstalk between the slit membrane-associated proteins and cytoskeletal components inside the podocyte foot processes. Our study shows that LASP-1, an actin-binding protein, is highly expressed in podocytes. Electron microscopy studies demonstrate that LASP-1 is found at the slit membrane suggesting a role in anchoring slit membrane components to the actin cytoskeleton. Live cell imaging experiments with transfected podocytes reveal that LASP-1 is either part of a highly dynamic granular complex or a static, actin cytoskeleton-bound protein. We identify CD2AP as a novel LASP-1 binding partner that regulates its association with the actin cytoskeleton. Activation of the renin-angiotensin-aldosterone system, which is crucial for podocyte function, leads to phosphorylation and altered localization of LASP-1. In vivo studies using the Drosophila nephrocyte model indicate that Lasp is necessary for the slit membrane integrity and functional filtration.
MeSH term(s)	Actin Cytoskeleton/physiology ; Animals ; Cell Membrane/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/physiology ; Kidney/physiology ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Phosphorylation ; Podocytes/physiology
Chemical Substances	Drosophila Proteins ; Lasp protein, Drosophila ; Microfilament Proteins
Language	English
Publishing date	2020-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201901443R
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Angiotensin II regulates phosphorylation of actin-associated proteins in human podocytes.

Schenk, Laura K / Möller-Kerutt, Annika / Klosowski, Rafael / Wolters, Dirk / Schaffner-Reckinger, Elisabeth / Weide, Thomas / Pavenstädt, Hermann / Vollenbröker, Beate

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2017 Volume 31, Issue 11, Page(s) 5019–5035

Abstract: Within the kidney, angiotensin II (AngII) targets different cell types in the vasculature, tubuli, and glomeruli. An important part of the renal filtration barrier is composed of podocytes with their actin-rich foot processes. In this study, we used ... ...

Abstract	Within the kidney, angiotensin II (AngII) targets different cell types in the vasculature, tubuli, and glomeruli. An important part of the renal filtration barrier is composed of podocytes with their actin-rich foot processes. In this study, we used stable isotope labeling with amino acids in cell culture coupled to mass spectrometry to characterize relative changes in the phosphoproteome of human podocytes in response to short-term treatment with AngII. In 4 replicates, we identified a total of 17,956 peptides that were traceable to 2081 distinct proteins. Bioinformatic analyses revealed that among the increasingly phosphorylated peptides are predominantly peptides that are related to actin filaments, cytoskeleton, lamellipodia, mammalian target of rapamycin, and MAPK signaling. Among others, this screening approach highlighted the increased phosphorylation of actin-bundling protein, l-plastin (LCP1). AngII-dependent phosphorylation of LCP1 in cultured podocytes was mediated by the kinases ERK, p90 ribosomal S6 kinase, PKA, or PKC. LCP1 phosphorylation increased filopodia formation. In addition, treatment with AngII led to LCP1 redistribution to the cell margins, membrane ruffling, and formation of lamellipodia. Our data highlight the importance of AngII-triggered actin cytoskeleton-associated signal transduction in podocytes.-Schenk, L. K., Möller-Kerutt, A., Klosowski, R., Wolters, D., Schaffner-Reckinger, E., Weide, T., Pavenstädt, H., Vollenbröker, B. Angiotensin II regulates phosphorylation of actin-associated proteins in human podocytes.
Language	English
Publishing date	2017-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201700142R
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Article: Cellular vacuolization caused by overexpression of the PIKfyve-binding deficient Vac14

Schulze, Ulf / Vollenbröker, Beate / Kühnl, Alexander / Granado, Daniel / Bayraktar, Samet / Rescher, Ursula / Pavenstädt, Hermann / Weide, Thomas

Biochimica et biophysica acta. Molecular cell research

2017 Volume 1864, Issue 5, Page(s) 749–759

Abstract: Phosphoinositides (PI) and converting enzymes are crucial determinants of organelle identity and morphology. One important endolysosomal specific PI is PI(3,5) ... ...

Abstract	Phosphoinositides (PI) and converting enzymes are crucial determinants of organelle identity and morphology. One important endolysosomal specific PI is PI(3,5)P
MeSH term(s)	Amino Acid Substitution/genetics ; Cells, Cultured ; Culture Media, Serum-Free/pharmacology ; Enzyme Inhibitors/pharmacology ; Food ; HEK293 Cells ; Humans ; Macrolides/pharmacology ; Membrane Proteins/genetics ; Podocytes/drug effects ; Podocytes/metabolism ; Podocytes/ultrastructure ; Up-Regulation/genetics ; Vacuolar Proton-Translocating ATPases/antagonists & inhibitors ; Vacuoles/drug effects ; Vacuoles/genetics
Chemical Substances	Culture Media, Serum-Free ; Enzyme Inhibitors ; Macrolides ; Membrane Proteins ; VAC14 protein, human ; bafilomycin A (116764-51-3) ; Vacuolar Proton-Translocating ATPases (EC 3.6.1.-)
Language	English
Publishing date	2017-02-16
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0167-4889 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0167-4889 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2017.02.012
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Uc I Zs.247: Show issues

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Article ; Online: The Hippo pathway is controlled by Angiotensin II signaling and its reactivation induces apoptosis in podocytes.

Wennmann, D O / Vollenbröker, B / Eckart, A K / Bonse, J / Erdmann, F / Wolters, D A / Schenk, L K / Schulze, U / Kremerskothen, J / Weide, T / Pavenstädt, H

Cell death & disease

2014 Volume 5, Page(s) e1519

Abstract: The Hippo pathway fulfills a crucial function in controlling the balance between proliferation, differentiation and apoptosis in cells. Recent studies showed that G protein-coupled receptors (GPCRs) serve as upstream regulators of Hippo signaling, that ... ...

Abstract	The Hippo pathway fulfills a crucial function in controlling the balance between proliferation, differentiation and apoptosis in cells. Recent studies showed that G protein-coupled receptors (GPCRs) serve as upstream regulators of Hippo signaling, that either activate or inactivate the Hippo pathway via the large tumor suppressor kinase (LATS) and its substrate, the co-transcription factor Yes-associated protein (YAP). In this study, we focused on the Angiotensin II type 1 receptor (AT1R), which belongs to the GPCR family and has an essential role in the control of blood pressure and water homeostasis. We found that Angiotensin II (Ang II) inactivates the pathway by decreasing the activity of LATS kinase; therefore, leading to an enhanced nuclear shuttling of unphosphorylated YAP in HEK293T cells. This shuttling of YAP is actin-dependent as disruption of the actin cytoskeleton inhibited dephosphorylation of LATS and YAP. Interestingly, in contrast to HEK293T cells, podocytes, which are a crucial component of the glomerular filtration barrier, display a predominant nuclear YAP localization in vivo and in vitro. Moreover, stimulation with Ang II did not alter Hippo pathway activity in podocytes, which show a deactivated pathway. Reactivation of the LATS kinase activity in podocytes resulted in an increased cytoplasmic YAP localization accompanied by a strong induction of apoptosis. Thus, our work indicates that the control of LATS activation and subsequent YAP localization is important for podocyte homeostasis and survival.
MeSH term(s)	Actin Cytoskeleton/chemistry ; Actin Cytoskeleton/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Angiotensin II/pharmacology ; Animals ; Apoptosis/genetics ; Cell Line, Transformed ; Cell Survival ; Gene Expression Regulation ; HEK293 Cells ; Homeostasis ; Humans ; Mice ; Mice, Transgenic ; Organ Specificity ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Phosphorylation ; Podocytes/cytology ; Podocytes/metabolism ; Primary Cell Culture ; Protein Transport ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Receptor, Angiotensin, Type 1/genetics ; Receptor, Angiotensin, Type 1/metabolism ; Signal Transduction ; Transcription Factors
Chemical Substances	Adaptor Proteins, Signal Transducing ; Phosphoproteins ; Receptor, Angiotensin, Type 1 ; Transcription Factors ; YAP1 protein, human ; Angiotensin II (11128-99-7) ; LATS1 protein, human (EC 2.7.1.-) ; Hippo protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2014-11-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/cddis.2014.476
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Article ; Online: Nephron-specific knockin of the PIKfyve-binding-deficient Vac14

Michgehl, Ulf / Skryabin, Boris V / Bayraktar, Samet / Vollenbröker, Beate / Ciarimboli, Giuliano / Heitplatz, Barbara / Van Marck, Veerle / Gröne, Hermann-Josef / Pavenstädt, Hermann / Weide, Thomas

American journal of physiology. Renal physiology

2018 Volume 315, Issue 5, Page(s) F1307–F1319

Abstract: Intracellular trafficking processes play a key role for the establishment and maintenance of membrane surfaces in renal epithelia. Therefore, dysfunctions of these trafficking processes could be key events and important determinants in the onset and ... ...

Abstract	Intracellular trafficking processes play a key role for the establishment and maintenance of membrane surfaces in renal epithelia. Therefore, dysfunctions of these trafficking processes could be key events and important determinants in the onset and progression of diseases. The presence of cellular vacuoles-observed in many histologic analyses of renal diseases-is a macroscopic hint for disturbed intracellular trafficking processes. However, how vacuoles develop and which intracellular pathways are directly affected remain largely unknown. Previous studies showed that in some cases, vacuolization is linked to malfunction of the Vac14 complex. This complex, including the scaffold protein Vac14, the lipid kinase PIKfyve, and its counteracting lipid phosphatase Fig4, regulates intracellular phosphatidylinositol phosphate levels, which in turn, control the maturation of early-into-late endosomes, as well as the processing of autophagosomes into autophagolysosomes. Here, we analyzed the role of Vac14 in mice and observed that the nephron-specific knockin of the PIKfyve-binding-deficient Vac14
MeSH term(s)	Albuminuria/genetics ; Albuminuria/metabolism ; Albuminuria/pathology ; Albuminuria/physiopathology ; Animals ; Cell Proliferation ; Dogs ; Endocytosis ; Female ; Gene Knock-In Techniques ; Genetic Predisposition to Disease ; Glomerular Mesangium/metabolism ; Glomerular Mesangium/physiopathology ; Glomerular Mesangium/ultrastructure ; Humans ; Kidney Tubules/metabolism ; Kidney Tubules/physiopathology ; Kidney Tubules/ultrastructure ; Madin Darby Canine Kidney Cells ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Phenotype ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Binding ; Protein Transport ; Signal Transduction ; Transcytosis
Chemical Substances	Membrane Proteins ; VAC14 protein, human ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Pikfyve protein, mouse (EC 2.7.1.137)
Language	English
Publishing date	2018-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00191.2018
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Article: Determination of cyclosporine and its metabolites in blood via HPLC-MS and correlation to clinically important parameters.

Vollenbroeker, B / Koch, J-H / Fobker, M / Suwelack, B / Hohage, H / Müller, U

Transplantation proceedings

2005 Volume 37, Issue 4, Page(s) 1741–1744

Abstract: The narrow therapeutic window of the immunosuppressive drug cyclosporine (CsA), the interindividual variability of its metabolism, and the immunosuppressive activity/toxicity of some metabolites require investigation to correlate the parent substance and ...

Abstract	The narrow therapeutic window of the immunosuppressive drug cyclosporine (CsA), the interindividual variability of its metabolism, and the immunosuppressive activity/toxicity of some metabolites require investigation to correlate the parent substance and its metabolites and observed clinical parameters. Improved knowledge about these correlations may improve postoperative treatment of transplant patients. To observe such correlation therapeutic drug monitoring was performed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) on 202 blood samples of kidney transplant patients. As CsA and its metabolites are preferably bound to lipoproteins in vivo, sample preparation included protein precipitation, solid phase extraction, and separation on a reversed phase column. Mass-spectrometric detection by an electrospray ionization chamber made the detection and quantification of the sodium adducts of CsA and its metabolites AM1, AM1c, DihydroAM1, AM19, and AM4N possible. With the presented HPLC-MS method, rapid information was achieved about the specific metabolization in a patient. Statistical computations related CsA and its metabolite concentrations to clinically important blood parameters. Significant correlation to the blood level of bilirubin and liver enzymes confirmed the presumed hepatotoxic potential of CsA and some metabolites. Furthermore, a strong correlation of AM19 to CRP and IL6 was observerd. These parameters may influence the prognosis for atherosclerosis, inflammation, and chronic allograft nephropathy.
MeSH term(s)	Alanine Transaminase/blood ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Chromatography, High Pressure Liquid/methods ; Creatinine/blood ; Cyclosporine/blood ; Cyclosporine/pharmacokinetics ; Humans ; Immunosuppressive Agents/blood ; Immunosuppressive Agents/pharmacokinetics ; Kidney Transplantation/immunology ; Kidney Transplantation/physiology ; L-Lactate Dehydrogenase/blood ; Mass Spectrometry ; Reproducibility of Results
Chemical Substances	Immunosuppressive Agents ; Cyclosporine (83HN0GTJ6D) ; Creatinine (AYI8EX34EU) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; Aspartate Aminotransferases (EC 2.6.1.1) ; Alanine Transaminase (EC 2.6.1.2) ; Bilirubin (RFM9X3LJ49)
Language	English
Publishing date	2005-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	82046-5
ISSN	1873-2623 ; 0041-1345
ISSN (online)	1873-2623
ISSN	0041-1345
DOI	10.1016/j.transproceed.2005.03.149
Database	MEDical Literature Analysis and Retrieval System OnLINE

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