Publications by authors named "Michael Zeisberg"

87 Publications

Histopathological Findings Predict Renal Recovery in Severe ANCA-Associated Vasculitis Requiring Intensive Care Treatment.

Front Med (Lausanne) 2020 9;7:622028. Epub 2021 Feb 9.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Renal involvement is a common and severe complication of AAV as it can cause ESRD. Histopathological subgrouping and ARRS are helpful to predict long-term ESRD in patients with AAV. Because a subgroup of critically ill patients with severe AAV present with deterioration of kidney function requiring RRT at admission, we here aimed to evaluate histopathological findings and predictive value of Berden's histopathological subgrouping and ARRS for severity of AKI and requirement of RRT during the short-term clinical course in critically ill patients requiring intensive care treatment and predictors for short-term renal recovery in patients requiring RRT. A subgroup of 15/46 (32. 6%) AAV patients with biopsy-proven AAV required RRT during the short-term course of disease, associated with requirement of critical care treatment. While histopathological subgrouping and ARRS were associated with requirement of acute RRT, presence of global glomerular scarring was the strongest predictor of failure to recover from RRT after initiation of remission induction therapy. This new aspect requires further investigation in a prospective controlled setting for therapeutic decision making especially in this subgroup.
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http://dx.doi.org/10.3389/fmed.2020.622028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900153PMC
February 2021

Variable Expression of Programmed Cell Death Protein 1-Ligand 1 in Kidneys Independent of Immune Checkpoint Inhibition.

Front Immunol 2020 21;11:624547. Epub 2021 Jan 21.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Context: Due to recent advantages in cancer therapy, immune checkpoint inhibitors (ICIs) are new classes of drugs targeting programmed cell death protein 1 (PD-1) or its ligand programmed cell death protein 1-ligand 1 (PD-L1) used in many cancer therapies. Acute interstitial nephritis (AIN) is a potential and deleterious immune-related adverse events (irAE) in the kidney observed in patients receiving ICIs and the most common biopsy-proven diagnosis in patients who develop acute kidney injury (AKI). Based on previous reports, AIN in patients receiving ICIs is associated with tubular positivity for PD-L1, implicating that PD-L1 positivity reflects susceptibility to develop renal complications with these agents. It remains unclear if PD-L1 positivity is acquired specifically during ICI therapy or expressed independently in the kidney.

Methods: PD-L1 was analyzed in experimental mouse models of ischemia-reperfusion injury (IRI), folic acid-induced nephropathy (FAN), unilateral ureteral obstruction (UUO), and nephrotoxic serum nephritis (NTN) by immunostaining, SDS-PAGE, and subsequent immunoblotting. In addition, we included a total number of 87 human kidney samples (six renal biopsies with AIN related to ICI therapy, 13 nephrectomy control kidneys, and 68 ICI-naïve renal biopsies with various underlying kidney diseases to describe PD-L1 expression.

Results: We here report distinct PD-L1 expression in renal compartments in multiple murine models of kidney injury and human cases with various underlying kidney diseases, including ICI-related AIN and renal pathologies independent of ICI therapy. PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. In addition, we provide evidence that tubular PD-L1 positivity in the kidney is associated with detection of urinary PD-L1 tubular epithelial cells.

Conclusion: Our study implicates that PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. Because non-invasive detection of PD-L1 cells in corresponding urine samples correlates with intrarenal PD-L1 positivity, it is attractive to speculate that further non-invasive detection of PD-L1 cells may identify patients at risk for ICI-related AIN.
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http://dx.doi.org/10.3389/fimmu.2020.624547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858644PMC
January 2021

Cytokine adsorption therapy in lymphoma-associated hemophagocytic lymphohistiocytosis and allogeneic stem cell transplantation.

J Artif Organs 2021 Jan 18. Epub 2021 Jan 18.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.

Lymphoma-associated Hemophagocytic lymphohistiocytosis (HLH) represents a severe complication of disease progression, mediated through cytokine release from the lymphoma cells. Cytokine adsorption may contribute as a supportive treatment to stabilize organ function by reduction of cytokine levels. So far, no experiences of cytokine adsorption and simultaneous stem cell transplantation were published. We report the case of a patient with aggressive lymphoma secondary to chronic lymphocytic leukemia with rapidly progressive HLH (Richter's transformation) upon conditioning chemotherapy prior to allogeneic stem cell transplantation (ASCT). Continuous hemodiafiltration was initiated in the treatment of shock with acute renal failure, lactacidosis and need for high-dose catecholamine therapy, integrating an additional cytokine-adsorbing filter (CytoSorb®) to reduce cytokine levels. This was followed by scheduled allogenic stem cell transplantation. We observed a marked decrease in interleukin-6 plasma levels, associated with a reduced need for vasopressor therapy and organ function stabilization. Hematopoietic engraftment was present at day 14 post-ASCT, leading to disease-free discharge at day 100 post-transplantation. Cytokine adsorption may serve as a safe adjunct to HLH/sepsis treatment during allogeneic stem cell transplantation. Clinical studies are required to make future treatment recommendations.
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http://dx.doi.org/10.1007/s10047-020-01244-2DOI Listing
January 2021

The Secretome Analysis of Activated Human Renal Fibroblasts Revealed Beneficial Effect of the Modulation of the Secreted Peptidyl-Prolyl Cis-Trans Isomerase A in Kidney Fibrosis.

Cells 2020 07 18;9(7). Epub 2020 Jul 18.

Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany.

The secretome is an important mediator in the permanent process of reciprocity between cells and their environment. Components of secretome are involved in a large number of physiological mechanisms including differentiation, migration, and extracellular matrix modulation. Alteration in secretome composition may therefore trigger cell transformation, inflammation, and diseases. In the kidney, aberrant protein secretion plays a central role in cell activation and transition and in promoting renal fibrosis onset and progression. Using comparative proteomic analyses, we investigated in the present study the impact of cell transition on renal fibroblast cells secretome. Human renal cell lines were stimulated with profibrotic hormones and cytokines, and alterations in secretome were investigated using proteomic approaches. We identified protein signatures specific for the fibrotic phenotype and investigated the impact of modeling secretome proteins on extra cellular matrix accumulation. The secretion of peptidyl-prolyl cis-trans isomerase A (PPIA) was demonstrated to be associated with fibrosis phenotype. We showed that the in-vitro inhibition of PPIA with ciclosporin A (CsA) resulted in downregulation of PPIA and fibronectin (FN1) expression and significantly reduced their secretion. Knockdown studies of PPIA in a three-dimensional (3D) cell culture model significantly impaired the secretion and accumulation of the extracellular matrix (ECM), suggesting a positive therapeutic effect on renal fibrosis progression.
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http://dx.doi.org/10.3390/cells9071724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407823PMC
July 2020

Clinical Efficacy of Routinely Administered Belimumab on Proteinuria and Neuropsychiatric Lupus.

Front Med (Lausanne) 2020 27;7:222. Epub 2020 May 27.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Belimumab (BEL) is a monoclonal antibody approved for the treatment of active systemic lupus erythematosus (SLE) but not for lupus nephritis (LN) and neuropsychiatric systemic lupus erythematosus (NPSLE). We aimed to assess BEL's effects on these severe, potentially life-threatening manifestations. Retrospective observational cohort study using routine clinical data in a case series of patients with SLE receiving BEL. Sixteen patients received BEL therapy for active SLE. Nine were excluded because they had no LN or NPSLE. Six suffered from LN, and one patient had NPSLE. All LN patients received BEL in addition to standard therapy including glucocorticoids, hydroxychloroquine, and mycophenolate mofetil in five cases, and tacrolimus in one case. Three patients with proteinuria >1,000 mg/g creatinine responded well (one complete, two partial renal responses); all other patients had decreasing proteinuria and a reduction in anti-dsDNA levels. The patient with NPSLE who had failed previous therapies had persistent clinical improvement of cutaneous and neuropsychiatric manifestations. There was one mild allergic reaction and one lower respiratory tract infection, but no other adverse events. One patient discontinued therapy due to a lack of improvement in clinical symptoms, another because of clinical remission. In our series, BEL led to a decrease of proteinuria in patients with proteinuria of more than 1,000 mg/g creatinine despite standard of care treatment, and led to a marked clinical improvement in one patient with NPSLE. No adverse events were observed. Routinely administered BEL shows clinical efficacy on non-approved manifestations, but careful patient selection is warranted.
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http://dx.doi.org/10.3389/fmed.2020.00222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267006PMC
May 2020

Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis.

Sci Signal 2020 06 9;13(635). Epub 2020 Jun 9.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

Endothelial-to-mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of (which encodes Twist) or (which encodes Snail) in VE-cadherin or Tie1 endothelial cells inhibited the emergence of EndMT and improved kidney fibrosis in two different kidney injury/fibrosis mouse models. Suppression of EndMT limited peritubular vascular leakage, reduced tissue hypoxia, and preserved tubular epithelial health and function. Hypoxia, which was exacerbated by EndMT, resulted in increased Myc abundance in tubular epithelial cells, enhanced glycolysis, and suppression of fatty acid oxidation. Pharmacological suppression or epithelial-specific genetic ablation of Myc in tubular epithelial cells ameliorated fibrosis and restored renal parenchymal function and metabolic homeostasis. Together, these findings demonstrate a functional role for EndMT in the response to kidney capillary endothelial injury and highlight the contribution of endothelial-epithelial cross-talk in the development of kidney fibrosis with a potential for therapeutic intervention.
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http://dx.doi.org/10.1126/scisignal.aaz2597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790440PMC
June 2020

Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer.

Cell Rep 2020 06;31(9):107701

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer, in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1α and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.
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http://dx.doi.org/10.1016/j.celrep.2020.107701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339325PMC
June 2020

CRISPR/Cas Derivatives as Novel Gene Modulating Tools: Possibilities and In Vivo Applications.

Int J Mol Sci 2020 Apr 25;21(9). Epub 2020 Apr 25.

Department of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.

The field of genome editing started with the discovery of meganucleases (e.g., the LAGLIDADG family of homing endonucleases) in yeast. After the discovery of transcription activator-like effector nucleases and zinc finger nucleases, the recently discovered clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated proteins (Cas) system has opened a new window of applications in the field of gene editing. Here, we review different Cas proteins and their corresponding features including advantages and disadvantages, and we provide an overview of the different endonuclease-deficient Cas protein (dCas) derivatives. These dCas derivatives consist of an endonuclease-deficient Cas9 which can be fused to different effector domains to perform distinct in vitro applications such as tracking, transcriptional activation and repression, as well as base editing. Finally, we review the in vivo applications of these dCas derivatives and discuss their potential to perform gene activation and repression in vivo, as well as their potential future use in human therapy.
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http://dx.doi.org/10.3390/ijms21093038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246536PMC
April 2020

Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1.

Theranostics 2020 4;10(9):3905-3924. Epub 2020 Mar 4.

Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.

: Cardiac fibrosis is an integral constituent of every form of chronic heart disease, and persistence of fibrosis reduces tissue compliance and accelerates the progression to heart failure. Relaxin-2 is a human hormone, which has various physiological functions such as mediating renal vasodilation in pregnancy. Its recombinant form Serelaxin has recently been tested in clinical trials as a therapy for acute heart failure but did not meet its primary endpoints. The aim of this study is to examine whether Serelaxin has an anti-fibrotic effect in the heart and therefore could be beneficial in chronic heart failure. : We utilized two different cardiac fibrosis mouse models (ascending aortic constriction (AAC) and Angiotensin II (ATII) administration via osmotic minipumps) to assess the anti-fibrotic potential of Serelaxin. Histological analysis, immunofluorescence staining and molecular analysis were performed to assess the fibrosis level and indicate endothelial cells which are undergoing EndMT. TGFβ1-induced endothelial-to-mesenchymal transition (EndMT) assays were performed in human coronary artery endothelial cells and mouse cardiac endothelial cells (MCECs) and were examined using molecular methods. Chromatin immunoprecipitation-qPCR assay was utilized to identify the Serelaxin effect on chromatin remodeling in the promoter region in MCECs. : Our results demonstrate a significant and dose-dependent anti-fibrotic effect of Serelaxin in the heart in both models. We further show that Serelaxin mediates this effect, at least in part, through inhibition of EndMT through the endothelial Relaxin family peptide receptor 1 (RXFP1). We further demonstrate that Serelaxin administration is able to increase its own receptor expression (RXFP1) through epigenetic regulation in form of histone modifications by attenuating TGFβ-pSMAD2/3 signaling in endothelial cells. : This study is the first to identify that Serelaxin increases the expression of its own receptor RXFP1 and that this mediates the inhibition of EndMT and cardiac fibrosis, suggesting that Serelaxin may have a beneficial effect as anti-fibrotic therapy in chronic heart failure.
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http://dx.doi.org/10.7150/thno.38640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086357PMC
March 2020

Rheopheresis for Digital Ulcers and Raynaud's Phenomenon in Systemic Sclerosis Refractory to Conventional Treatments.

Front Med (Lausanne) 2019 18;6:208. Epub 2019 Sep 18.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Raynaud's phenomenon (RP) is almost universally present in patients with Systemic Sclerosis (SSc). RP represents a generalized vasculopathy and potentially lead to digital ulcers (DU), which may be complicated by superinfection, tissue necrosis, and limb loss. We report the analysis of an extracorporeal procedure in a 36-year-old female patient with diffuse SSc with refractory RP and DU despite treatment with diltiazem, candesartan, sildenafil, and intravenous iloprost. We performed rheopheresis (RheoP), a variant of double-filtration plasmapheresis, as a potential new treatment option for refractory patients despite optimal medical therapy. We performed two RheoP per week every 4 weeks for a total of 3 months. Clinical improvement in DU healing occurred with no adverse events directly related to the treatment. While there was no reduction in the number of Raynaud attacks with RheoP, a significant reduction of the duration of attacks from a median of 15 (5-45, 95% CI 10-15) to 7 (3-30, 95% CI 6-10) minutes with an improvement of the Raynaud Condition Score (RCS) improved from 4 to 2. In conclusion, RheoP is a feasible and potentially beneficial treatment modality in patients with refractory RP and DU. We propose that RheoP should be investigated in a larger number of patients in a clinical trial setting.
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http://dx.doi.org/10.3389/fmed.2019.00208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759692PMC
September 2019

Causal Connections From Chronic Kidney Disease to Cardiac Fibrosis.

Semin Nephrol 2018 11;38(6):629-636

Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), Partner Site, Goettingen, Germany. Electronic address:

Cardiovascular disease and heart failure are the primary cause of morbidity and mortality in patients with chronic kidney disease. Because impairment of kidney function correlates with heart failure and cardiac fibrosis, a kidney-heart axis is suspected. Although our understanding of the underlying mechanisms still is evolving, the possibility that kidney-heart messengers could be intercepted offers ample reason to focus on this clinically highly relevant problem. Here, we review the current knowledge of how kidney injury causes heart failure and fibrosis.
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http://dx.doi.org/10.1016/j.semnephrol.2018.08.007DOI Listing
November 2018

Modulation of NCAM/FGFR1 signaling suppresses EMT program in human proximal tubular epithelial cells.

PLoS One 2018 1;13(11):e0206786. Epub 2018 Nov 1.

Institute of Pathology, University of Belgrade-Faculty of Medicine, Belgrade, Serbia.

Neural cell adhesion molecule (NCAM) and fibroblast growth factor receptor 1 (FGFR1) cross-talk have been involved in epithelial-to-mesenchymal transition (EMT) process during carcinogenesis. Since EMT also contributes to maladaptive repair and parenchymal damage during renal fibrosis, we became encouraged to explore the role of NCAM/FGFR1 signaling as initiating or driving forces of EMT program in cultured human proximal tubular epithelial cells (TECs). TECs stimulated with TGF-β1 (10ng/mL) was used as an established in vitro EMT model. TGF-β1 downstream effectors were detected in vitro, as well as in 50 biopsies of different human kidney diseases to explore their in vivo correlation. NCAM/FGFR1 signaling and its modulation by FGFR1 inhibitor PD173074 (100nM) were analyzed by light microscopy, immunolabeling, qRT-PCR and scratch assays. Morphological changes associated with EMT appeared 48h after TGF-ß1 treatment and was clearly apparent after 72 hours, followed by loss of CDH1 (encoding E-Cadherin) and transcriptional induction of SNAI1 (SNAIL), SNAI2 (SLUG), TWIST1, MMP2, MMP9, CDH2 (N-Cadherin), ITGA5 (integrin-α5), ITGB1 (integrin-β1), ACTA2 (α-SMA) and S100A4 (FSP1). Moreover, at the early stage of EMT program (24 hours upon TGF-β1 exposure), transcriptional induction of several NCAM isoforms along with FGFR1 was observed, implicating a mechanistic link between NCAM/FGFR1 signaling and induction of EMT. These assumptions were further supported by the inhibition of the EMT program after specific blocking of FGFR1 signaling by PD173074. Finally, there was evidence for an in vivo TGF-β1 pathway activation in diseased human kidneys and correlation with impaired renal excretory functions. Collectively, NCAM/FGFR1 signaling appears to be involved in the initial phase of TGF-ß1 initiated EMT which can be effectively suppressed by application of FGFR inhibitor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206786PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211750PMC
April 2019

High-fidelity CRISPR/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis.

Nat Commun 2018 08 29;9(1):3509. Epub 2018 Aug 29.

German Center for Cardiovascular Research (DZHK) Partner Site, Göttingen, Germany.

While suppression of specific genes through aberrant promoter methylation contributes to different diseases including organ fibrosis, gene-specific reactivation technology is not yet available for therapy. TET enzymes catalyze hydroxymethylation of methylated DNA, reactivating gene expression. We here report generation of a high-fidelity CRISPR/Cas9-based gene-specific dioxygenase by fusing an endonuclease deactivated high-fidelity Cas9 (dHFCas9) to TET3 catalytic domain (TET3CD), targeted to specific genes by guiding RNAs (sgRNA). We demonstrate use of this technology in four different anti-fibrotic genes in different cell types in vitro, among them RASAL1 and Klotho, both hypermethylated in kidney fibrosis. Furthermore, in vivo lentiviral delivery of the Rasal1-targeted fusion protein to interstitial cells and of the Klotho-targeted fusion protein to tubular epithelial cells each results in specific gene reactivation and attenuation of fibrosis, providing gene-specific demethylating technology in a disease model.
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http://dx.doi.org/10.1038/s41467-018-05766-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115451PMC
August 2018

The "rapid atrial swirl sign" for assessing central venous catheters: Performance by medical residents after limited training.

PLoS One 2018 16;13(7):e0199345. Epub 2018 Jul 16.

Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany.

Rationale: Central venous catheter (CVC) placement is a standard procedure in critical care. Ultrasound guidance during placement is recommended by current guidelines, but there is no consensus on the best method for evaluating the correct CVC tip position. Recently, the "rapid atrial swirl sign" (RASS) has been investigated in a limited number of studies.

Objectives: We performed a prospective diagnostic accuracy study of focused echocardiography for the evaluation of CVC tip position in our medical ICU and IMC units.

Methods: We performed a prospective diagnostic accuracy study in 100 patients admitted to the Intensive Care Unit and Intermediate Care Unit at our center. The first 10 subjects were assessed by one staff physician investigator (reference cohort), the remaining 90 patients by different residents (test cohort). All patients received a post-procedural chest radiograph (CXR) as gold standard. CVC placement was assessed with focused echocardiography performed by residents after a short training session. A rapid opacification of the right atrium (RASS) after injection of 10 mL of normal saline was regarded as "positive", flush after more than two seconds was defined as "delayed", no flush was a "negative" test result.

Measurements And Main Results: Overall sensitivity of the RASS was 100% (95% CI 73.54-100%), specificity was 94.32% (CI 87.24-98.13%). Positive and negative predictive values were 70.59% (CI 44.04-89.09%) and 100% (CI 95.65-100%), respectively. Median time for echocardiographic testing was 5 minutes (1-28) in the whole cohort, CXRs were available after 49.5 minutes (13-254). Interrater agreement of the RASS was 0.77 (Cohen's kappa), Measurement of CVC tip position was not different between two observers. Test characteristics were similar among differently experienced residents.

Conclusions: Presence of the RASS by focused echocardiography showed excellent sensitivity and specificity and was equally performed by residents after minimal training. In patients with a positive RASS, routine CXR can be safely omitted, reducing time, costs and radiation exposure. A negative RASS should lead to a search for misplaced catheters.

Clinical Trial Registration: The study was registered with www.clinicaltrials.gov (NCT02661607).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047781PMC
January 2019

Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure.

J Clin Invest 2018 07 11;128(7):3053-3070. Epub 2018 Jun 11.

Department of Nephrology and Rheumatology.

Progression of chronic kidney disease associated with progressive fibrosis and impaired tubular epithelial regeneration is still an unmet biomedical challenge because, once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. Prompted by various studies across multiple organs demonstrating that preconditioning regimens to induce endogenous regenerative mechanisms protect various organs from later incurring acute injuries, we here aimed to gain insights into the molecular mechanisms underlying successful protection and to explore whether such pathways could be utilized to inhibit progression of chronic organ injury. We identified a protective mechanism controlled by the transcription factor ARNT that effectively inhibits progression of chronic kidney injury by transcriptional induction of ALK3, the principal mediator of antifibrotic and proregenerative bone morphogenetic protein-signaling (BMP-signaling) responses. We further report that ARNT expression itself is controlled by the FKBP12/YY1 transcriptional repressor complex and that disruption of such FKBP12/YY1 complexes by picomolar FK506 at subimmunosuppressive doses increases ARNT expression, subsequently leading to homodimeric ARNT-induced ALK3 transcription. Direct targeting of FKBP12/YY1 with in vivo morpholino approaches or small molecule inhibitors, including GPI-1046, was equally effective for inducing ARNT expression, with subsequent activation of ALK3-dependent canonical BMP-signaling responses and attenuated chronic organ failure in models of chronic kidney disease, and also cardiac and liver injuries. In summary, we report an organ-protective mechanism that can be pharmacologically modulated by immunophilin ligands FK506 and GPI-1046 or therapeutically targeted by in vivo morpholino approaches.
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http://dx.doi.org/10.1172/JCI89632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025987PMC
July 2018

Chromatin dynamics at the core of kidney fibrosis.

Matrix Biol 2018 08 21;68-69:194-229. Epub 2018 Feb 21.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Georg August University, Göttingen, Germany. Electronic address:

Progression of chronic kidney disease is a principal challenge in Nephrology, as effective therapies to halt or even reverse established lesion are not available yet. While numerous growth factors and environmental stimuli that drive progression of chronic kidney disease are present within the fibrotic microenvironment, the effector cells' genetic information needs to be accessible in order to enable the pro-fibrotic response. As more than 2 m of DNA encoding the genetic information is crammed as protein-DNA complex called chromatin within the nucleus of each cell, an accessible chromatin state is a prerequisite in the hierarchical order of events to enable production of fibrotic proteins and fibrotic cellular responses. Here, we review contribution and underlying mechanisms of chromatin organization, histone modifications and DNA methylation to progression of chronic kidney disease, provide recent evidence for cell type-specific cell fate decisions and discuss possible diagnostic and therapeutic applications.
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http://dx.doi.org/10.1016/j.matbio.2018.02.015DOI Listing
August 2018

3D virtual histology of murine kidneys -high resolution visualization of pathological alterations by micro computed tomography.

Sci Rep 2018 01 23;8(1):1407. Epub 2018 Jan 23.

Institute of Diagnostic and Interventional Radiology, University Medical Center Goettingen, Robert Koch Str. 40, Goettingen, Lower Saxony, 37075, Germany.

The increasing number of patients with end stage chronic kidney disease not only calls for novel therapeutics but also for pioneering research using convincing preclinical disease models and innovative analytical techniques. The aim of this study was to introduce a virtual histology approach using micro computed tomography (µCT) for the entire murine kidney in order to close the gap between single slice planar histology and a 3D high resolution dataset. An ex vivo staining protocol based on phosphotungstic acid diffusion was adapted to enhance renal soft tissue x-ray attenuation. Subsequent CT scans allowed (i) the detection of the renal cortex, medulla and pelvis in greater detail, (ii) the analysis of morphological alterations, (iii) the quantification of the volume as well as the radio-opacity of these portions and (iv) the quantification of renal fibrotic remodeling based on altered radio-opacity using the unilateral ureteral obstruction model. Thus, virtual histology based on PTA contrast enhanced CT will in future help to refine the outcome of preclinical research on kidney associated murine disease models.
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http://dx.doi.org/10.1038/s41598-018-19773-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780475PMC
January 2018

Increased Whole Blood Viscosity Is Associated with the Presence of Digital Ulcers in Systemic Sclerosis: Results from a Cross-Sectional Pilot Study.

Autoimmune Dis 2017 29;2017:3529214. Epub 2017 Nov 29.

Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, USA.

Objective: To investigate the role of whole blood viscosity in digital ulcer (DU) development in patients with diffuse and limited Systemic sclerosis.

Methods: A convenience sample of patients with Systemic sclerosis (SSc) was selected from the adult Rheumatology clinic at the University of Chicago. The study group consisted of patients with SSc (with ulcers present, a history of ulcers, and no ulcers); the control group consisted of matched healthy Rheumatology clinic staff. WBV was measured using a scanning capillary viscometer at different shear rates (1-1000 1/s).

Results: Whole blood viscosity as measured by a scanning capillary viscometer was increased in patients with SSc compared to healthy controls ( < 0.0001). Additionally, patients with present DU had significantly higher whole blood viscosity when compared to patients with a history of DU and patients with no history of DU ( < 0.0001). These findings were most pronounced at lower shear rates between 1 and 10 1/s.

Conclusion: Whole blood viscosity might be a contributing factor in DU development in patients with SSc. Further studies with larger patient cohorts are required to fully evaluate how increased WBV contributes to the development of DU and whether the currently available treatment options improve the microcirculation by influencing WBV.
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http://dx.doi.org/10.1155/2017/3529214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727567PMC
November 2017

Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression.

Kidney Int 2017 01 28;91(1):157-176. Epub 2016 Sep 28.

Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; German Center for Cardiovascular Research, Göttingen, Germany. Electronic address:

Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure-lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure-lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.
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http://dx.doi.org/10.1016/j.kint.2016.07.042DOI Listing
January 2017

Partial Epithelial-to-Mesenchymal Transition and Other New Mechanisms of Kidney Fibrosis.

Trends Endocrinol Metab 2016 10 29;27(10):681-695. Epub 2016 Jun 29.

Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA. Electronic address:

Kidney fibrosis is the unavoidable consequence of chronic kidney disease irrespective of the primary underlying insult. It is a complex phenomenon governed by the interplay between different cellular components and intricate networks of signaling pathways, which together lead to loss of renal functionality and replacement of kidney parenchyma with scar tissue. An immense effort has recently been made to understand the molecular and cellular mechanisms leading to kidney fibrosis. The cellular protagonists of this process include myofibroblasts, tubular epithelial cells, endothelial cells, and immune cells. We discuss here the most recent findings, including partial epithelial-to-mesenchymal transition (EMT), in the initiation and progression of tissue fibrosis and chronic kidney disease (CKD). A deep understanding of these mechanisms will allow the development of effective therapies.
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http://dx.doi.org/10.1016/j.tem.2016.06.004DOI Listing
October 2016

Differentiation of functional endothelial cells from human induced pluripotent stem cells: A novel, highly efficient and cost effective method.

Differentiation 2016 Oct - Nov;92(4):225-236. Epub 2016 Jun 4.

Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg August University, 37075 Göttingen, Germany; DZHK (German Centre for Cardiovascular Research) Partner Site Göttingen, 37075 Göttingen, Germany. Electronic address:

Endothelial cells derived from human induced pluripotent stem cells (hiPSC- EC) are of significant value for research on human vascular development, in vitro disease models and drug screening. Here we report an alternative, highly efficient and cost-effective simple three step method (mesoderm induction, endothelial cell differentiation and endothelial cell expansion) to differentiate hiPSC directly into endothelial cells. We demonstrate that efficiency of described method to derive CD31+ and VE-Cadherin+ double positive cells is higher than 80% in 12 days. Most notably we established that hiPSC-EC differentiation efficacy depends on optimization of both mesoderm differentiation and endothelial cell differentiation steps.
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http://dx.doi.org/10.1016/j.diff.2016.05.004DOI Listing
August 2017

Hypoxia-induced endothelial-mesenchymal transition is associated with RASAL1 promoter hypermethylation in human coronary endothelial cells.

FEBS Lett 2016 04 21;590(8):1222-33. Epub 2016 Apr 21.

Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.

Cardiac fibrosis is integral in chronic heart disease, and one of the cellular processes contributing to cardiac fibrosis is endothelial-to-mesenchymal transition (EndMT). We recently found that hypoxia efficiently induces human coronary artery endothelial cells (HCAEC) to undergo EndMT through a hypoxia inducible factor-1α (HIF1α)-dependent pathway. Promoter hypermethylation of Ras-Gap-like protein 1 (RASAL1) has also been recently associated with EndMT progression and cardiac fibrosis. Our findings suggest that HIF1α and transforming growth factor (TGF)/SMAD signalling pathways synergistically regulate hypoxia-induced EndMT through both DNMT3a-mediated hypermethylation of RASAL1 promoter and direct SNAIL induction. The findings indicate that multiple cascades may be activated simultaneously to mediate hypoxia-induced EndMT.
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http://dx.doi.org/10.1002/1873-3468.12158DOI Listing
April 2016

DNMT1 and HDAC2 Cooperate to Facilitate Aberrant Promoter Methylation in Inorganic Phosphate-Induced Endothelial-Mesenchymal Transition.

PLoS One 2016 27;11(1):e0147816. Epub 2016 Jan 27.

Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.

While phosphorus in the form of inorganic or organic phosphate is critically involved in most cellular functions, high plasma levels of inorganic phosphate levels have emerged as independent risk factor for cardiac fibrosis, cardiovascular morbidity and decreased life-expectancy. While the link of high phosphate and cardiovascular disease is commonly explained by direct cellular effects of phospho-regulatory hormones, we here explored the possibility of inorganic phosphate directly eliciting biological responses in cells. We demonstrate that human coronary endothelial cells (HCAEC) undergo an endothelial-mesenchymal transition (EndMT) when exposed to high phosphate. We further demonstrate that such EndMT is initiated by recruitment of aberrantly phosphorylated DNMT1 to the RASAL1 CpG island promoter by HDAC2, causing aberrant promoter methylation and transcriptional suppression, ultimately leading to increased Ras-GTP activity and activation of common EndMT regulators Twist and Snail. Our studies provide a novel aspect for known adverse effects of high phosphate levels, as eukaryotic cells are commonly believed to have lost phosphate-sensing mechanisms of prokaryotes during evolution, rendering them insensitive to extracellular inorganic orthophosphate. In addition, our studies provide novel insights into the mechanisms underlying specific targeting of select genes in context of fibrogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147816PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729486PMC
July 2016

High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation.

Biochem Biophys Res Commun 2016 Apr 14;472(3):459-64. Epub 2016 Jan 14.

Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), Göttingen, Germany. Electronic address:

Phosphate is an essential constituent of critical cellular functions including energy metabolism, nucleic acid synthesis and phosphorylation-dependent cell signaling. Increased plasma phosphate levels are an independent risk factor for lowered life-expectancy as well as for heart and kidney failure. Nevertheless, direct cellular effects of elevated phosphate concentrations within the microenvironment are poorly understood and have been largely neglected in favor of phosphor-regulatory hormones. Because interstitial fibrosis is the common determinant of chronic progressive kidney disease, and because fibroblasts are major mediators of fibrogenesis, we here explored the effect of high extracellular phosphate levels on renal fibroblasts. We demonstrate that high inorganic phosphate directly induces fibrotic fibroblast activation associated with increased proliferative activity, increased expression of α-smooth muscle actin and increased synthesis of type I collagen. We further demonstrate that such fibroblast activation is dependent on phosphate influx, aberrant phosphorylation of DNA methyltransferase DNMT1 and aberrant CpG island promoter methylation. In summary, our studies demonstrate that elevated phosphate concentrations induce pro-fibrotic fibroblast activation independent of phospho-regulatory hormones.
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http://dx.doi.org/10.1016/j.bbrc.2016.01.077DOI Listing
April 2016

Proteomic analysis of embryonic kidney development: Heterochromatin proteins as epigenetic regulators of nephrogenesis.

Sci Rep 2015 Sep 11;5:13951. Epub 2015 Sep 11.

Department of Nephrology and Rheumatology, Georg-August University Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany.

Elucidation of the mechanisms underlying the nephrogenesis will boost enormously the regenerative medicine. Here we performed 2-D gel-based comparative proteome analyses of rat embryonic kidney from different developmental stages. Out of 288 non-redundant identified proteins, 102 were common in all developmental stages. 86% of the proteins found in E14 and E16 were identical, in contrast only 37% of the identified proteins overlap between E14 and P1. Bioinformatics analysis suggests developmental stage-specific pathway activation and highlighted heterochromatin protein 1 (Cbx1, Cbx3, Cbx5) and Trim28 as potential key players in nephrogenesis. These are involved in the epigenetic regulation of gene silencing and were down-regulated in the course of kidney development. Trim28 is a potential epigenetic regulator of the branching inhibitor Bmp4. Silencing of Trim28 in cultured kidneys resulted in branching arrest. In contrast knockdown of Cbx5 was associated with abnormal ureteric bud growth and slight impairment of branching. ChIP analysis showed that the H3K9me3 distribution on Bmp4 promoters at E14 and E19 inversely correlate with mRNA expression levels. The concentrated expression-pattern of heterochromatin proteins and the negative impact of their silencing on kidney development, suggest an important role in reciprocal and inductive signaling between the ureteric bud and the metanephric mesenchyme.
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http://dx.doi.org/10.1038/srep13951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566080PMC
September 2015

Precision renal medicine: a roadmap towards targeted kidney fibrosis therapies.

Fibrogenesis Tissue Repair 2015 1;8:16. Epub 2015 Sep 1.

Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany ; German Center for Cardiovascular Research (DZHK), Robert Koch Street 40, Göttingen, Germany.

Based on extensive pre-clinical achievements over the past decades, it appears to be due time for a successful clinical translation in the renal fibrosis field-but what is the quickest road to get there? In light of the recent launch of the Precision Medicine Initiative and success of molecularly informed drugs in oncology, we here discuss what it may take to bring molecularly targeted anti-fibrotic to clinical use in chronic progressive kidney disease.
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http://dx.doi.org/10.1186/s13069-015-0033-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556008PMC
September 2015

Variable Expression of Neural Cell Adhesion Molecule Isoforms in Renal Tissue: Possible Role in Incipient Renal Fibrosis.

PLoS One 2015 1;10(9):e0137028. Epub 2015 Sep 1.

Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg-August University, Göttingen, Germany.

Rare neural cell adhesion molecule (NCAM) positive cells have been previously described within the normal human adult kidney interstitium, speculating that they could increase in the interstitium with incipient interstitial renal fibrosis (IRF). In the present study, among 93 biopsy samples of various kidney diseases, NCAM+ interstitial cells were detected in 62.4% cases. An increased number of NCAM+ cells was significantly observed only in incipient IRF compared to normal renal tissues and advanced IRF stages (p<0.001), independently of underlying diseases (p = 0.657). All three major NCAM isoforms' RT-PCR bands were visible either in normal or in kidneys with incipient IRF, albeit their mRNA expression levels measured by qRT-PCR were different. Applying qRT-PCR on pure NCAM+ cells population, obtained by laser capture microdissection, significant mRNA over-expression of NCAM140kD isoform was found in NCAM+ cells within incipient IRF (p = 0.004), while NCAM120kD and NCAM180kD isoforms were not changed significantly (p = 0.750; p = 0.704; respectively). Simultaneously, qRT-PCR also showed significant αSMA (p = 0.014) and SLUG (p = 0.004) mRNAs up-regulation within the NCAM+ cells of incipient IRF, as well as highly decreased matrix metalloproteinases (MMP) -2 and -9 mRNAs (p = 0.028; p = 0.036; respectively). However, using double immunofluorescence MMP-9 could still be detectable on the protein level in rare NCAM+ cells within the incipient IRF. Further characterization of NCAM+ cells by double immunofluorescent labeling revealed their association with molecules involved in fibrosis. Fibroblast growth factor receptor 1 (FGFR1) and α5β1 integrin were extensively expressed on NCAM+ cells within the incipient IRF areas, whereas human epididymis protein-4 (HE4) was found to be present in few NCAM+ cells of both normal and interstitium with incipient fibrosis. Heterogeneity of NCAM+ interstitial cells in normal and incipient IRF, concerning molecules related to fibrosis and variable expression of NCAM isoforms, could suggest diverse role of NCAM+ cells in homeostasis and in regulation of renal fibrosis in diseased kidneys.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137028PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556687PMC
May 2016

Evidence for antifibrotic incretin-independent effects of the DPP-4 inhibitor linagliptin.

Kidney Int 2015 Sep;88(3):429-31

Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg August University, Göttingen, Germany.

Among gliptins, linagliptin is unique, because decreased glomerular filtration rate does not require dose reduction. Linagliptin was originally developed to lower blood glucose by inhibiting dipeptidyl peptidase-4 (DPP-4). However, DPP-4 has numerous additional substrates, and thus gliptins possess a vast range of additional off-target effects. Shi et al. report that linagliptin directly targets interaction of DPP-4 with integrin β1, preventing endothelial-mesenchymal transition and ultimately renal fibrosis, providing additional rationale for use of linagliptin in diabetic nephropathy.
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http://dx.doi.org/10.1038/ki.2015.175DOI Listing
September 2015

Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis.

Nat Med 2015 Sep 3;21(9):998-1009. Epub 2015 Aug 3.

Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-β1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration. In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of the EMT program in TECs during chronic renal injury represents a potential anti-fibrosis therapy.
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http://dx.doi.org/10.1038/nm.3902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587560PMC
September 2015

Snail Is a Direct Target of Hypoxia-inducible Factor 1α (HIF1α) in Hypoxia-induced Endothelial to Mesenchymal Transition of Human Coronary Endothelial Cells.

J Biol Chem 2015 Jul 13;290(27):16653-64. Epub 2015 May 13.

From the Departments of Cardiology and Pneumology and DZHK (German Centre for Cardiovascular Research) partner site, 37075 Göttingen, Germany

Endothelial to mesenchymal transition (EndMT) was originally described in heart development where the endocardial endothelial cells that line the atrioventricular canal undergo an EndMT to form the endocardial mesenchymal cushion that later gives rise to the septum and mitral and tricuspid valves. In the postnatal heart specifically, endothelial cells that originate from the endocardium maintain increased susceptibility to undergo EndMT as remnants from their embryonic origin. Such EndMT involving adult coronary endothelial cells contributes to microvascular rarefaction and subsequent chronification of hypoxia in the injured heart, ultimately leading to cardiac fibrosis. Although in most endothelial beds hypoxia induces tip cell formation and sprouting angiogenesis, here we demonstrate that hypoxia is a stimulus for human coronary endothelial cells to undergo phenotypic changes reminiscent of EndMT via a mechanism involving hypoxia-inducible factor 1α-induced activation of the EndMT master regulatory transcription factor SNAIL. Our study adds further evidence for the unique susceptibility of endocardium-derived endothelial cells to undergo EndMT and provides novel insights into how hypoxia contributes to progression of cardiac fibrosis. Additional studies may be required to discriminate between distinct sprouting angiogenesis and EndMT responses of different endothelial cells populations.
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http://dx.doi.org/10.1074/jbc.M115.636944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505417PMC
July 2015