Janina Müller‐Deile

Universitätsklinikum Erlangen

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Mario Schiffer

Friedrich-Alexander-Universität Erlangen-Nürnberg

Hermann Haller

Medizinische Hochschule Hannover

Nina Sopel

Friedrich-Alexander-Universität Erlangen-Nürnberg

Heiko Schenk

Medizinische Hochschule Hannover

Patricia Schröder

Mount Desert Island Biological Laboratory

Jenny Nyström

University of Gothenburg

Hermann Haller

Medizinische Hochschule Hannover

Christoph Daniel

Friedrich-Alexander-Universität Erlangen-Nürnberg

Victoria Rose

Friedrich-Alexander-Universität Erlangen-Nürnberg

Alexandra Ohs

Universitätsklinikum Erlangen

Cooperative Institutions

Medizinische Hochschule Hannover

Friedrich-Alexander-Universität Erlangen-Nürnberg

Universitätsklinikum Erlangen

Universität Hamburg

RELX Group (United States)

Heidelberg University

Hypertension Institute

University Medical Center Hamburg-Eppendorf

Nanjing Medical University

Charité - Universitätsmedizin Berlin

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A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes

Cells (2022)

Nina Sopel Alexandra Ohs Mario Schiffer Janina Müller‐Deile

Nephronectin (NPNT) is an extracellular matrix protein in the glomerular basement membrane that is produced by podocytes and is important for the integrity of the glomerular filtration barrier. Upregulated transforming growth factor β (TGF-β) and altered NPNT are seen in different glomerular diseases. TGF-β downregulates NPNT and upregulates NPNT-targeting microRNAs (miRs). However, the pathways involved were previously unknown. By using selective inhibitors of the canonical, SMAD-dependent, and non-canonical TGF-β pathways, we investigated NPNT transcription, translation, secretion, and regulation through miRs in podocytes. TGF-β decreased NPNT mRNA and protein in cultured human podocytes. TGF-β-dependent regulation of NPNT was meditated through intracellular signaling pathways. Under baseline conditions, non-canonical pathways predominantly regulated NPNT post-transcriptionally. Podocyte NPNT secretion, however, was not dependent on canonical or non-canonical TGF-β pathways. The canonical TGF-β pathway was also dispensable for NPNT regulation after TGF-β stimulation, as TGF-β was still able to downregulate NPNT in the presence of SMAD inhibitors. In contrast, in the presence of different non-canonical pathway inhibitors, TGF-β stimulation did not further decrease NPNT expression. Moreover, distinct non-canonical TGF-β pathways mediated TGF-β-induced upregulation of NPNT-targeting miR-378a-3p. Thus, we conclude that post-transcriptional fine-tuning of NPNT expression in podocytes is mediated predominantly through non-canonical TGF-β pathways.

10.3390/cells11010149

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Citations (5)

IPNA Clinical Practice Recommendations for the Diagnosis and Management of Children with Steroid-resistant Nephrotic Syndrome

Nephrology and Dialysis (2020)

Agnes Trautmann Marina Vivarelli Susan Samuel Debbie S. Gipson Aditi Sinha

Clinical Practice

10.28996/2618-9801-2020-4-435-473

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Citations (17)

Role of endothelial microRNA 155 on capillary leakage in systemic inflammation

Critical Care (2021)

Valerie Etzrodt Temitayo O. Idowu Heiko Schenk Benjamin Seeliger Antje Prasse

Abstract Background Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage. Methods SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance. Results Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects. Conclusions We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target.

Knockout mouse

Vascular permeability

Ex vivo

10.1186/s13054-021-03500-0

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Effects of Nanoplastic Particles on the Kidney

Journal of the American Society of Nephrology (2024)

Melina Yarbakht M. A. Hinrichs Marie Hecker Mustafa Kocademir Zahra Mirzaei

10.1681/asn.2024b4g2q3f2

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Online Kt/V Monitoring in Haemodialysis by UV Absorbance: Variations during Intra-Dialytic Meals

Blood Purification (2014)

Janina Müller‐Deile Ralf Lichtinghagen H. L. Haller Roland Schmitt

The aim of this study was to analyse if intra-dialytic food intake may lead to changes in online Kt/V.Forty patients were analysed using haemodialysis machines with integrated online Kt/V monitoring based on UV absorbance or ionic dialysance. Kt/V was monitored before, during and after food intake. Samples of dialysate were analysed for urea, uric acid, creatinine and glucose levels.Food intake was associated with a significant decrease in relative Kt/V when determined by UV absorbance. The drop in Kt/V was independent of changes in blood pressure or body posture. No significant changes in online Kt/V were found using the ionic dialysance method. Dialysate samples showed a continuous clearance of urea, uric acid and creatinine during meals but a rapid increase in glucose.Our data suggest that the short meal-associated decrease in online Kt/V as measured by UV absorbance does not represent a true decline in Kt/V but might reflect an intermittent increase in UV-absorbing dialysed solutes.

Kt/V

Absorbance

10.1159/000358212

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Citations (22)

Preeclampsia from a renal point of view: Insides into disease models, biomarkers and therapy

World Journal of Nephrology (2014)

Janina Müller‐Deile

Proteinuria is a frequently detected symptom, found in 20% of pregnancies.A common reason for proteinuria in pregnancy is preeclampsia.To diagnose preeclampsia clinically and to get new insights into the pathophysiology of the disease it is at first essential to be familiar with conditions in normal pregnancy.Animal models and biomarkers can help to learn more about disease conditions and to find new treatment strategies.In this article we review the changes in kidney function during normal pregnancy and the differential diagnosis of proteinuria in pregnancy.We summarize different pathophysiological theories of preeclampsia with a special focus on the renal facets of the disease.We describe the current animal models and give a broad overview of different biomarkers that were reported to predict preeclampsia or have a prognostic value in preeclampsia cases.We end with a summary of treatment options for preeclampsia related symptoms including the use of plasmapheresis as a rescue therapy for so far refractory preeclampsia.Most of these novel biomarkers for preeclampsia are not yet implemented in clinical use.Therefore, we recommend using proteinuria (measured by UPC ratio) as a screening parameter for preeclampsia.Delivery is the only curative treatment for preeclampsia.In early preeclampsia the primary therapy goal is to prolong pregnancy until a state were the child has an acceptable chance of survival after delivery.

10.5527/wjn.v3.i4.169

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Citations (49)

Renal Involvement in Preeclampsia: Similarities to VEGF Ablation Therapy

Journal of Pregnancy (2010)

Janina Müller‐Deile Mario Schiffer

Glomerular VEGF expression is critical for the maintenance and function of an intact filtration barrier. Alterations in glomerular VEGF bioavailability result in endothelial as well as in podocyte damage. Renal involvement in preeclampsia includes proteinuria, podocyturia, elevated blood pressure, edema, glomerular capillary endotheliosis, and thrombotic microangiopathy. At least the renal signs, symptoms, and other evidence can sufficiently be explained by reduced VEGF levels. The aim of this paper was to summarize our pathophysiological understanding of the renal involvement of preeclampsia and point out similarities to the renal side effects of VEGF-ablation therapy.

Thrombotic microangiopathy

Pathophysiology

Glomerulosclerosis

10.1155/2011/176973

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Citations (41)

MP126PROTEINURIA DETECTION IN ZEBRAFISH LARVAE USING HIGH SENSITIVITY PROTEIN CHIP ANALYSIS AND TANDEM MASS SPECTROMETRY

Nephrology Dialysis Transplantation (2016)

Heiko Schenk Janina Müller‐Deile Andreas Pich Pat Schroder Lynne Staggs

10.1093/ndt/gfw185.17

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MiR-200b Induces ZEB1-Mediated Upregulation of Matriptase and Affects Expression of Podocin: A Proposed Mechanism of Podocyte Effacement and Proteinuria in Diabetic Kidney Disease

Journal of the American Society of Nephrology (2023)

Ramesh Tati Janina Müller‐Deile Anna Walentinsson Nina Sopel Miguel Carracedo

Podocin

10.1681/asn.20233411s1836a

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Glomerular Endothelial Cell-Derived miR-200c Impairs Glomerular Homeostasis by Targeting Podocyte VEGF-A

International Journal of Molecular Sciences (2022)

Raluca Ursu Nina Sopel Alexandra Ohs Ramesh Tati Lisa Buvall

Deciphering the pathophysiological mechanisms of primary podocytopathies that can lead to end-stage renal disease and increased mortality is an unmet need. Studying how microRNAs (miRs) interfere with various signaling pathways enables identification of pathomechanisms, novel biomarkers and potential therapeutic options. We investigated the expression of miR-200c in urine from patients with different renal diseases as a potential candidate involved in podocytopathies. The role of miR-200c for the glomerulus and its potential targets were studied in cultured human podocytes, human glomerular endothelial cells and in the zebrafish model. miR-200c was upregulated in urine from patients with minimal change disease, membranous glomerulonephritis and focal segmental glomerulosclerosis and also in transforming growth factor beta (TGF-β) stressed glomerular endothelial cells, but not in podocytes. In zebrafish, miR-200c overexpression caused proteinuria, edema, podocyte foot process effacement and glomerular endotheliosis. Although zinc finger E-Box binding homeobox 1/2 (ZEB1/2), important in epithelial to mesenchymal transition (EMT), are prominent targets of miR-200c, their downregulation did not explain our zebrafish phenotype. We detected decreased vegfaa/bb in zebrafish overexpressing miR-200c and could further prove that miR-200c decreased VEGF-A expression and secretion in cultured human podocytes. We hypothesize that miR-200c is released from glomerular endothelial cells during cell stress and acts in a paracrine, autocrine, as well as context-dependent manner in the glomerulus. MiR-200c can cause glomerular damage most likely due to the reduction of podocyte VEGF-A. In contrast, miR-200c might also influence ZEB expression and therefore EMT, which might be important in other conditions. Therefore, we propose that miR-200c-mediated effects in the glomerulus are context-sensitive.

Renal glomerulus

Glomerulosclerosis

10.3390/ijms232315070

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Citations (5)