René Krüger

Universitätsklinikum Erlangen

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i-10 index

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Co-Authors

Mario Schiffer

Friedrich-Alexander-Universität Erlangen-Nürnberg

Johannes Schödel

Universitätsklinikum Erlangen

Stephanie Naas

Universitätsklinikum Erlangen

Steffen Grampp

Friedrich-Alexander-Universität Erlangen-Nürnberg

Karl X. Knaup

Friedrich-Alexander-Universität Erlangen-Nürnberg

Julia Naas

Medical University of Vienna

Victoria Rose

Friedrich-Alexander-Universität Erlangen-Nürnberg

Andre Kraus

Friedrich-Alexander-Universität Erlangen-Nürnberg

Janina Müller‐Deile

Universitätsklinikum Erlangen

Miguel Fuentes‐Chandía

Friedrich-Alexander-Universität Erlangen-Nürnberg

Cooperative Institutions

RELX Group (United States)

107

Friedrich-Alexander-Universität Erlangen-Nürnberg

Universitätsklinikum Erlangen

Charité - Universitätsmedizin Berlin

Universität Hamburg

University Medical Center Hamburg-Eppendorf

Freie Universität Berlin

Humboldt-Universität zu Berlin

Heidelberg University

Istituti di Ricovero e Cura a Carattere Scientifico

Author Statistics

Papers

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When Mechanical Stress Matters: Generation of Polyploid Giant Cancer Cells in Tumor-like Microcapsules

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Adrian Bühler René Krüger Mahshid Monavari Miguel Fuentes‐Chandía Ralf Palmisano

Abstract In this work, we studied the generation and rising of polyploid cancer cells as a product of mechanical stress. To this purpose, MCF7 breast cancer cells were cultured on 2D ( i.e . flasks, or flat hydrogels), and in 3D milieus ( i.e . Spheroids, or immobilized within alginate-gelatin microbeads, named in this work as tumor-like microcapsules), and further analyzed by biophysical and genetic methods (i.e. single-cell Traction Force Microscopy and RNA-seq respectively). Our results show that MCF7 cells preconditioned onto 2D surfaces exhibit a low number of polynucleated cells, while their culture in 3D environments triggered their progressive generation with time. Genetic studies enabled us to determine that polyploid cells found in tumor-like microcapsules are likely originated by cell-cell fusion and disrupted cytokinesis, showing most of the genetic markers for Polyploid Giant Cancer Cell, while cells cultured as spheroids seem to be likely generated by other mechanisms, such as cell cannibalisms, entosis, or emperipolesis. Our outcomes strongly suggest that both mechanical stress and confinement are required to stimulate cell polyploidy, which can be easily addressed by the immobilization of breast cancer cells in tumor-like microcapsules.

Polyploid

Spheroid

10.1101/2022.09.22.508846

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Citations (3)

The renal cancer risk allele at 14q24.2 activates a novel hypoxia-inducible transcription factor-binding enhancer of DPF3 expression

Journal of Biological Chemistry (2022)

Johanna Protze Stephanie Naas René Krüger Christine Stöhr Andre Kraus

Evolution of clear cell renal cell carcinoma is guided by dysregulation of hypoxia-inducible transcription factor (HIF) pathways following loss of the von Hippel-Lindau tumor suppressor protein. Renal cell carcinoma (RCC)-associated polymorphisms influence HIF-DNA interactions at enhancers of important oncogenes thereby modulating the risk of developing renal cancer. A strong signal of genome-wide association with RCC was determined for the single nucleotide polymorphism (SNP) rs4903064, located on chr14q.24.2 within an intron of DPF3, encoding for Double PHD Fingers 3, a member of chromatin remodeling complexes; however, it is unclear how the risk allele operates in renal cells. In this study, we used tissue specimens and primary renal cells from a large cohort of RCC patients to examine the function of this polymorphism. In clear cell renal cell carcinoma tissue, isolated tumor cells as well as in primary renal tubular cells, in which HIF was stabilized, we determined genotype-specific increases of DPF3 mRNA levels and identified that the risk SNP resides in an active enhancer region, creating a novel HIF-binding motif. We then confirmed allele-specific HIF binding to this locus using chromatin immunoprecipitation of HIF subunits. Consequentially, HIF-mediated DPF3 regulation was dependent on the presence of the risk allele. Finally, we show that DPF3 deletion in proximal tubular cells retarded cell growth, indicating potential roles for DPF3 in cell proliferation. Our analyses suggest that the HIF pathway differentially operates on a SNP-induced hypoxia-response element at 14q24.2, thereby affecting DPF3 expression, which increases the risk of developing renal cancer.

Hypoxia-Inducible Factors

Chromatin immunoprecipitation

10.1016/j.jbc.2022.101699

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Citations (12)

Ex Vivo-Derived Human-Induced Pluripotent Stem Cell (hiPSC) Podocytes from a Patient with Genetic Focal Segmental Glomerulosclerosis with an INF2 Mutation

Journal of the American Society of Nephrology (2024)

Victoria Rose Daniel Fink René Krüger Johannes Schödel Mario Schiffer

Ex vivo

Glomerulosclerosis

10.1681/asn.2024xjaq7vqq

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Citations (0)

KidneyGPS: a user-friendly web application to help prioritize kidney function genes and variants based on evidence from genome-wide association studies

BMC Bioinformatics (2023)

Kira J. Stanzick Klaus Stark Mathias Gorski Johannes Schödel René Krüger

Abstract Background Genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with kidney function. By combining these findings with post-GWAS information (e.g., statistical fine-mapping to identify independent association signals and to narrow down signals to causal variants; or different sources of annotation data), new hypotheses regarding physiology and disease aetiology can be obtained. These hypotheses need to be tested in laboratory experiments, for example, to identify new therapeutic targets. For this purpose, the evidence obtained from GWAS and post-GWAS analyses must be processed and presented in a way that they are easily accessible to kidney researchers without specific GWAS expertise. Main Here we present KidneyGPS, a user-friendly web-application that combines genetic variant association for estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics consortium with annotation of (i) genetic variants with functional or regulatory effects (“SNP-to-gene” mapping), (ii) genes with kidney phenotypes in mice or human (“gene-to-phenotype”), and (iii) drugability of genes (to support re-purposing). KidneyGPS adopts a comprehensive approach summarizing evidence for all 5906 genes in the 424 GWAS loci for eGFR identified previously and the 35,885 variants in the 99% credible sets of 594 independent signals. KidneyGPS enables user-friendly access to the abundance of information by search functions for genes, variants, and regions. KidneyGPS also provides a function (“GPS tab”) to generate lists of genes with specific characteristics thus enabling customizable Gene Prioritisation (GPS). These specific characteristics can be as broad as any gene in the 424 loci with a known kidney phenotype in mice or human; or they can be highly focussed on genes mapping to genetic variants or signals with particularly with high statistical support. KidneyGPS is implemented with RShiny in a modularized fashion to facilitate update of input data ( https://kidneygps.ur.de/gps/ ). Conclusion With the focus on kidney function related evidence, KidneyGPS fills a gap between large general platforms for accessing GWAS and post-GWAS results and the specific needs of the kidney research community. This makes KidneyGPS an important platform for kidney researchers to help translate in silico research results into in vitro or in vivo research.

Genome-wide Association Study

10.1186/s12859-023-05472-0

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Citations (1)

When Mechanical Stress Matters: Generation of Polyploid Giant Cancer Cells in Tumor‐Like Microcapsules

Advanced Functional Materials (2024)

Yasmin Antonelli René Krüger Adrian Büehler Mahshid Monavari Miguel Fuentes‐Chandía

Abstract Biofabrication techniques enable the performance of bioinspired three‐dimensional (3D) matrices resembling primary tumors. To validate their reliability, embedded cells may express complex biophysical responses. Among others, the emergence of tumor heterogeneity and the generation of Polyploid Giant Cancer Cells (PGCC), as a result of the mechanical stress, are two of the most challenging hallmarks to resemble in vitro. Here, these phenomena are studied in cells cultured on two‐dimensional (2D) flasks, in 3D spheroids, or immobilized within 3D polymer‐based tumor‐like microcapsules. These results show that cells cultured in 3D microcapsules exhibited an enhanced biomechanical heterogeneity, a higher number of PGCC, and an increased exertion of cell‐matrix attachment forces with respect to the other two experimental conditions. Additionally, cells isolated from tumor‐like microcapsules redistribute and align the cytoplasmatic protein Caveolin‐1, and upregulate markers involved in cell proliferation (i.e., Ki67), metastasis (i.e., TGF‐β1, TGF‐β‐R2), and epithelial to mesenchymal transition, to name a few. These hallmarks are barely described in the past as a result of the confinement and mechanical stress. Thus, in this work it is demonstrated that both the mechanical stress and confinement are required to stimulate cell polyploidy and biomechanical heterogeneity, which can be easily addressed by immobilizing breast cancer cells in tumor‐like microcapsules.

Biofabrication

Polyploid

mechanobiology

Spheroid

10.1002/adfm.202311139

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Citations (2)

Stabilization of Hypoxia-Inducible Factors Leads to Profound Epigenetic Changes in Primary Human Tubular Cells

Journal of the American Society of Nephrology (2021)

René Krüger Mario Schiffer Johannes Schödel Stephanie Naas

Universitatsklinikum Erlangen Medizinische Klinik 4 Nephrologie und Hypertensiologie, Erlangen, Germany.

Hypoxia

Primary (astronomy)

Hypoxia-Inducible Factors

10.1681/asn.20213210s1191c

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Citations (0)

Identification of RNASE1 as a Novel Contributor to Cytoskeleton Remodeling in Podocytes

Journal of the American Society of Nephrology (2024)

Patricia Bolaños-Palmieri René Krüger Evren U. Azeloglu Mario Schiffer

Identification

10.1681/asn.2024423jenx6

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Hypoxia controls expression of kidney-pathogenicMUC1variants

Life Science Alliance (2023)

Stephanie Naas René Krüger Karl X. Knaup Julia Naas Steffen Grampp

The interplay between genetic and environmental factors influences the course of chronic kidney disease (CKD). In this context, genetic alterations in the kidney disease gene MUC1 (Mucin1) predispose to the development of CKD. These variations comprise the polymorphism rs4072037, which alters splicing of MUC1 mRNA, the length of a region with variable number of tandem repeats (VNTR), and rare autosomal-dominant inherited dominant-negative mutations in or 5' to the VNTR that causes autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1). As hypoxia plays a pivotal role in states of acute and chronic kidney injury, we explored the effects of hypoxia-inducible transcription factors (HIF) on the expression of MUC1 and its pathogenic variants in isolated primary human renal tubular cells. We defined a HIF-binding DNA regulatory element in the promoter-proximal region of MUC1 from which hypoxia or treatment with HIF stabilizers, which were recently approved for an anti-anemic therapy in CKD patients, increased levels of wild-type MUC1 and the disease-associated variants. Thus, application of these compounds might exert unfavorable effects in patients carrying MUC1 risk variants.

MUC1

Hypoxia

10.26508/lsa.202302078

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Citations (1)

Hypoxia induces polycystin-1 expression in the renal epithelium

Royal Society Open Science (2023)

Steffen Grampp Andre Kraus Kathrin Skoczynski Mario Schiffer René Krüger

Mutations in polycystin-1 which is encoded by the PKD1 gene are the main causes for the development of autosomal dominant polycystic kidney disease. However, only little is known about the physiological function of polycystin-1 and even less about the regulation of its expression. Here, we show that expression of PKD1 is induced by hypoxia and compounds that stabilize the hypoxia-inducible transcription factor (HIF) 1 α in primary human tubular epithelial cells. Knockdown of HIF subunits confirms HIF-1α-dependent regulation of polycystin-1 expression. Furthermore, HIF ChIP-seq reveals that HIF interacts with a regulatory DNA element within the PKD1 gene in renal tubule-derived cells. HIF-dependent expression of polycystin-1 can also be demonstrated in vivo in kidneys of mice treated with substances that stabilize HIF. Polycystin-1 and HIF-1 α have been shown to promote epithelial branching during kidney development. In line with these findings, we show that expression of polycystin-1 within mouse embryonic ureteric bud branches is regulated by HIF. Our finding links expression of one of the main regulators of accurate renal development with the hypoxia signalling pathway and provides additional insight into the pathophysiology of polycystic kidney disease.

PKD1

Hypoxia

10.1098/rsos.220992

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Citations (1)

S-File1_diff_expressed_genes from Hypoxia induces polycystin-1 expression in the renal epithelium

Figshare (2023)

Steffen Grampp Andre Kraus Kathrin Skoczynski Mario Schiffer René Krüger

differentially expressed genes upon HIF-stimulation in human primary tubule cells

Hypoxia

10.6084/m9.figshare.22785906

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Citations (0)