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Article ; Online: The authors reply.

Mühlig, Anne K / Schmitt, Claus-Peter / Oh, Jun

2024 Volume 105, Issue 2, Page(s) 390

Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Letter
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2023.10.028
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Article ; Online: Precision nephrology: from molecular diagnostics to an individualized therapy.

Mühlig, Anne K / Oh, Jun / Huber, Tobias B

Kidney international

2023 Volume 103, Issue 3, Page(s) 464–466

Abstract: The diagnosis of glomerular disease still mostly relies on the conventional histologic and immunohistochemical analysis of biopsies, thereby failing to provide a molecular disease understanding and stratification as the fundamental basis for an ... ...

Abstract	The diagnosis of glomerular disease still mostly relies on the conventional histologic and immunohistochemical analysis of biopsies, thereby failing to provide a molecular disease understanding and stratification as the fundamental basis for an individualized therapy. It is out of the question that nephrology will be transformed into a field of systemic molecular precision diagnostics and individualized therapies. However, the time scale and efficiency of such transformation will depend on more studies exemplifying successful translational strategies. The highly heterogeneous glomerular disease entities of minimal change disease and focal segmental glomerular sclerosis seem ideally suited to exploring and ensuring the advancement of an individualized precision nephrology.
MeSH term(s)	Humans ; Nephrology ; Pathology, Molecular ; Kidney Diseases/pathology ; Kidney Glomerulus/pathology ; Glomerulosclerosis, Focal Segmental/pathology
Language	English
Publishing date	2023-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2022.12.017
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Article ; Online: Collapsing Focal Segmental Glomerulosclerosis in Viral Infections.

Muehlig, Anne K / Gies, Sydney / Huber, Tobias B / Braun, Fabian

Frontiers in immunology

2022 Volume 12, Page(s) 800074

Abstract: Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration ... ...

Abstract	Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration of glomerular capillaries, the appearance of hyperplastic and hypertrophic podocytes and severe tubulointerstitial damage. Clinically, cFSGS patients present with acute kidney injury, nephrotic-range proteinuria and are at a high risk of rapid progression to irreversible kidney failure. cFSGS can be attributed to numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein-Barr-Virus, and parvovirus B19 and also drugs and severe ischemia. Risk variants of the APOL1 gene, predominantly found in people of African descent, increase the risk of developing cFSGS. Patients infected with the new Corona-Virus SARS-CoV-2 display an increased rate of acute kidney injury (AKI) in severe cases of COVID-19. Besides hemodynamic instability, cytokine mediated injury and direct viral entry and infection of renal epithelial cells contributing to AKI, there are emerging reports of cFSGS associated with SARS-CoV-2 infection in patients of mainly African ethnicity. The pathogenesis of cFSGS is proposed to be linked with direct viral infection of podocytes, as described for HIV-associated glomerulopathy. Nevertheless, there is growing evidence that the systemic inflammatory cascade, activated in acute viral infections like COVID-19, is a major contributor to the impairment of basic cellular functions in podocytes. This mini review will summarize the current knowledge on cFSGS associated with viral infections with a special focus on the influence of systemic immune responses and potential mechanisms propagating the development of cFSGS.
MeSH term(s)	Animals ; COVID-19/complications ; COVID-19/immunology ; COVID-19/virology ; Epithelial Cells/immunology ; Epithelial Cells/virology ; Glomerulosclerosis, Focal Segmental/etiology ; Glomerulosclerosis, Focal Segmental/immunology ; Glomerulosclerosis, Focal Segmental/virology ; Humans ; Immunity/immunology ; Kidney Glomerulus/immunology ; Kidney Glomerulus/virology ; Podocytes/immunology ; Podocytes/virology ; Proteinuria/etiology ; Proteinuria/immunology ; Proteinuria/virology ; SARS-CoV-2/immunology
Language	English
Publishing date	2022-01-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.800074
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Article: Levamisole in Children with Idiopathic Nephrotic Syndrome: Clinical Efficacy and Pathophysiological Aspects.

Mühlig, Anne K / Lee, Jun Young / Kemper, Markus J / Kronbichler, Andreas / Yang, Jae Won / Lee, Jiwon M / Shin, Jae Il / Oh, Jun

Journal of clinical medicine

2019 Volume 8, Issue 6

Abstract: Steroid sensitive nephrotic syndrome is one of the most common pediatric glomerular diseases. Unfortunately, it follows a relapsing and remitting course in the majority of cases, with 50% of all cases relapsing once or even more often. Most children with ...

Abstract	Steroid sensitive nephrotic syndrome is one of the most common pediatric glomerular diseases. Unfortunately, it follows a relapsing and remitting course in the majority of cases, with 50% of all cases relapsing once or even more often. Most children with idiopathic nephrotic syndrome respond initially to steroid therapy, nevertheless repeated courses for patients with relapses induce significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, levamisole, or rituximab. To reduce the relapse rate, several drugs have been used. Among these, levamisole has been considered the least toxic and least expensive therapy. Several randomized controlled trials (RCT) showed that levamisole is effective in reducing the relapse risk in steroid sensitive forms of nephrotic syndrome with a low frequency of side effects. Levamisole is a synthetic imidazothiazole derivative with immune-modulatory properties. In this article, we review recent data from randomized trials and observational studies to assess the efficacy of levamisole in frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome.
Language	English
Publishing date	2019-06-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm8060860
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Article ; Online: Lithocholic bile acid induces apoptosis in human nephroblastoma cells: a non-selective treatment option.

Trah, Julian / Arand, Jonas / Oh, Jun / Pagerols-Raluy, Laia / Trochimiuk, Magdalena / Appl, Birgit / Heidelbach, Hannah / Vincent, Deirdre / Saleem, Moin A / Reinshagen, Konrad / Mühlig, Anne K / Boettcher, Michael

Scientific reports

2020 Volume 10, Issue 1, Page(s) 20349

Abstract: Lithocholic bile acid (LCA) has been reported to selectively kill cancer cells within many tumor cell lines including neuroblastoma or glioblastoma. Wilms' tumor shares similarities with neuro- and glioblastoma. Hence, the aim of the study was to ... ...

Abstract	Lithocholic bile acid (LCA) has been reported to selectively kill cancer cells within many tumor cell lines including neuroblastoma or glioblastoma. Wilms' tumor shares similarities with neuro- and glioblastoma. Hence, the aim of the study was to evaluate the effects of LCA on nephroblastoma. To test the effects of LCA, nephroblastoma cell line WT CLS1 was used. SK NEP1 was tested as well. It was originally classified as a nephroblastoma cell line but was meanwhile reclassified as an ewing sarcoma cell line. As control cell lines HEK 293 from embryonic kidney and RC 124 from adult kidney tissue as well as podocytes were used. The effects were evaluated using proliferation assay, caspase activity assay, FACS and Western blot. LCA showed a dose and time-dependent selective effect inducing apoptosis in nephroblastoma cells. However, these effects were not limited to the nephroblastoma cell line but also affected control kidney cell lines and the sarcoma cells; only podocytes are significantly less affected by LCA (at dosages < 200 µm). There were no significant differences regarding the TGR5 receptor expression. The study showed that LCA has a strong, yet unselective effect on all used in vitro cell-lines, sparing the highly differentiated podocytes in lower concentrations. Further studies are needed to verify our results before dismissing LCA as an anti-cancer drug.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Apoptosis/genetics ; Caspase 3/genetics ; Caspase 3/metabolism ; Caspase 7/genetics ; Caspase 7/metabolism ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects ; Epithelial Cells/pathology ; Gene Expression Regulation, Neoplastic/drug effects ; HEK293 Cells ; Humans ; Lithocholic Acid/pharmacology ; Podocytes/drug effects ; Podocytes/pathology ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Antineoplastic Agents ; GPBAR1 protein, human ; Receptors, G-Protein-Coupled ; Lithocholic Acid (5QU0I8393U) ; CASP3 protein, human (EC 3.4.22.-) ; CASP7 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 7 (EC 3.4.22.-)
Language	English
Publishing date	2020-11-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-77436-w
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Article ; Online: The calcium-sensing receptor stabilizes podocyte function in proteinuric humans and mice.

Kidney international

2022 Volume 101, Issue 6, Page(s) 1186–1199

Abstract: Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria ... ...

Abstract	Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear. Here, a CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated calcium ion-influx, disrupted the actin cytoskeleton, and reduced cellular attachment and migration velocity. Adriamycin-induced proteinuria enhanced glomerular CaSR expression in wild-type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in adriamycin-treated podocyte-specific CaSR knockout mice compared to wild-type littermates. Co-treatment of wild-type mice with adriamycin and the calcimimetic cinacalcet reduced proteinuria in wild-type, but not in podocyte-specific CaSR knockout mice. Additionally, four children with nephrotic syndrome, whose parents objected to glucocorticoid therapy, were treated with cinacalcet for one to 33 days. Proteinuria declined transiently by up to 96%, serum albumin increased, and edema resolved. Thus, activation of podocyte CaSR regulates key podocyte functions in vitro and reduced toxin-induced proteinuria and glomerular damage in mice. Hence, our findings suggest a potential novel role of CaSR signaling in control of glomerular disease.
MeSH term(s)	Animals ; Calcium/metabolism ; Cinacalcet/pharmacology ; Cinacalcet/therapeutic use ; Doxorubicin/toxicity ; Humans ; Kidney Diseases/metabolism ; Mice ; Mice, Knockout ; Podocytes/metabolism ; Proteinuria/chemically induced ; Proteinuria/genetics ; Proteinuria/metabolism ; Receptors, Calcium-Sensing/genetics ; Receptors, Calcium-Sensing/metabolism
Chemical Substances	Receptors, Calcium-Sensing ; Doxorubicin (80168379AG) ; Calcium (SY7Q814VUP) ; Cinacalcet (UAZ6V7728S)
Language	English
Publishing date	2022-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2022.01.036
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Article ; Online: Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH.

Woestemeier, Anna / Scognamiglio, Pasquale / Zhao, Yu / Wagner, Jonas / Muscate, Franziska / Casar, Christian / Siracusa, Francesco / Cortesi, Filippo / Agalioti, Theodora / Müller, Simone / Sagebiel, Adrian / Konczalla, Leonie / Wahib, Ramez / Karstens, Karl-Frederick / Giannou, Anastasios D / Duprée, Anna / Wolter, Stefan / Wong, Milagros N / Mühlig, Anne K /

Bielecka, Agata A / Bansal, Vikas / Zhang, Tianran / Mann, Oliver / Puelles, Victor G / Huber, Tobias B / Lohse, Ansgar W / Izbicki, Jakob R / Palm, Noah W / Bonn, Stefan / Huber, Samuel / Gagliani, Nicola

JCI insight

2023 Volume 8, Issue 1

Abstract: A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of ... ...

Abstract	A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.
MeSH term(s)	Humans ; Non-alcoholic Fatty Liver Disease ; CD4-Positive T-Lymphocytes ; Fibrosis
Language	English
Publishing date	2023-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.153831
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Article ; Online: Podocytes Produce and Secrete Functional Complement C3 and Complement Factor H.

Mühlig, Anne K / Keir, Lindsay S / Abt, Jana C / Heidelbach, Hannah S / Horton, Rachel / Welsh, Gavin I / Meyer-Schwesinger, Catherine / Licht, Christoph / Coward, Richard J / Fester, Lars / Saleem, Moin A / Oh, Jun

Frontiers in immunology

2020 Volume 11, Page(s) 1833

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Complement Activation/immunology ; Complement C3/immunology ; Complement C3/metabolism ; Complement Factor H/immunology ; Complement Factor H/metabolism ; Humans ; Male ; Podocytes/immunology ; Podocytes/metabolism ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Complement C3 ; Complement Factor H (80295-65-4)
Language	English
Publishing date	2020-08-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01833
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Article ; Online: Lithocholic bile acid induces apoptosis in human nephroblastoma cells

Julian Trah / Jonas Arand / Jun Oh / Laia Pagerols-Raluy / Magdalena Trochimiuk / Birgit Appl / Hannah Heidelbach / Deirdre Vincent / Moin A. Saleem / Konrad Reinshagen / Anne K. Mühlig / Michael Boettcher

Scientific Reports, Vol 10, Iss 1, Pp 1-

a non-selective treatment option

2020 Volume 8

Abstract: Abstract Lithocholic bile acid (LCA) has been reported to selectively kill cancer cells within many tumor cell lines including neuroblastoma or glioblastoma. Wilms’ tumor shares similarities with neuro- and glioblastoma. Hence, the aim of the study was ... ...

Abstract	Abstract Lithocholic bile acid (LCA) has been reported to selectively kill cancer cells within many tumor cell lines including neuroblastoma or glioblastoma. Wilms’ tumor shares similarities with neuro- and glioblastoma. Hence, the aim of the study was to evaluate the effects of LCA on nephroblastoma. To test the effects of LCA, nephroblastoma cell line WT CLS1 was used. SK NEP1 was tested as well. It was originally classified as a nephroblastoma cell line but was meanwhile reclassified as an ewing sarcoma cell line. As control cell lines HEK 293 from embryonic kidney and RC 124 from adult kidney tissue as well as podocytes were used. The effects were evaluated using proliferation assay, caspase activity assay, FACS and Western blot. LCA showed a dose and time-dependent selective effect inducing apoptosis in nephroblastoma cells. However, these effects were not limited to the nephroblastoma cell line but also affected control kidney cell lines and the sarcoma cells; only podocytes are significantly less affected by LCA (at dosages < 200 µm). There were no significant differences regarding the TGR5 receptor expression. The study showed that LCA has a strong, yet unselective effect on all used in vitro cell-lines, sparing the highly differentiated podocytes in lower concentrations. Further studies are needed to verify our results before dismissing LCA as an anti-cancer drug.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH

Anna Woestemeier / Pasquale Scognamiglio / Yu Zhao / Jonas Wagner / Franziska Muscate / Christian Casar / Francesco Siracusa / Filippo Cortesi / Theodora Agalioti / Simone Müller / Adrian Sagebiel / Leonie Konczalla / Ramez Wahib / Karl-Frederick Karstens / Anastasios D. Giannou / Anna Duprée / Stefan Wolter / Milagros N. Wong / Anne K. Mühlig /

Agata A. Bielecka / Vikas Bansal / Tianran Zhang / Oliver Mann / Victor G. Puelles / Tobias B. Huber / Ansgar W. Lohse / Jakob R. Izbicki / Noah W. Palm / Stefan Bonn / Samuel Huber / Nicola Gagliani

JCI Insight, Vol 8, Iss

2023 Volume 1

Abstract	A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.
Keywords	Hepatology ; Immunology ; Medicine ; R
Subject code	570
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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