Dataset Information

A Multi-layered Quantitative In Vivo Expression Atlas of the Podocyte Unravels Kidney Disease Candidate Genes.

ABSTRACT: Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. Moreover, in vivo stable isotope labeling by amino acids uncovered surprisingly rapid synthesis of mitochondrial proteins under steady-state conditions that was perturbed under autophagy-deficient, disease-susceptible conditions. Integration of acquired omics dimensions suggested FARP1 as a candidate essential for podocyte function, which could be substantiated by genetic analysis in humans and knockdown experiments in zebrafish. This work exemplifies how the integration of multi-omics datasets can identify a framework of cell-type-specific features relevant for organ health and disease.

SUBMITTER: Rinschen MM

PROVIDER: S-EPMC5986710 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A Multi-layered Quantitative In Vivo Expression Atlas of the Podocyte Unravels Kidney Disease Candidate Genes.

Rinschen Markus M MM Gödel Markus M Grahammer Florian F Zschiedrich Stefan S Helmstädter Martin M Kretz Oliver O Zarei Mostafa M Braun Daniela A DA Dittrich Sebastian S Pahmeyer Caroline C Schroder Patricia P Teetzen Carolin C Gee HeonYung H Daouk Ghaleb G Pohl Martin M Kuhn Elisa E Schermer Bernhard B Küttner Victoria V Boerries Melanie M Busch Hauke H Schiffer Mario M Bergmann Carsten C Krüger Marcus M Hildebrandt Friedhelm F Dengjel Joern J Benzing Thomas T Huber Tobias B TB

Cell reports 20180501 8

Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. M ...[more]

PMID: 29791858

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Project description:Multi-atlas segmentation has been shown to be highly robust and accurate across an extraordinary range of potential applications. However, it is limited to the segmentation of structures that are anatomically consistent across a large population of potential target subjects (i.e., multi-atlas segmentation is limited to "in-atlas" applications). Herein, the authors propose a technique to determine the likelihood that a multi-atlas segmentation estimate is representative of the problem at hand, and, therefore, identify anomalous regions that are not well represented within the atlases.The authors derive a technique to estimate the out-of-atlas (OOA) likelihood for every voxel in the target image. These estimated likelihoods can be used to determine and localize the probability of an abnormality being present on the target image.Using a collection of manually labeled whole-brain datasets, the authors demonstrate the efficacy of the proposed framework on two distinct applications. First, the authors demonstrate the ability to accurately and robustly detect malignant gliomas in the human brain-an aggressive class of central nervous system neoplasms. Second, the authors demonstrate how this OOA likelihood estimation process can be used within a quality control context for diffusion tensor imaging datasets to detect large-scale imaging artifacts (e.g., aliasing and image shading).The proposed OOA likelihood estimation framework shows great promise for robust and rapid identification of brain abnormalities and imaging artifacts using only weak dependencies on anomaly morphometry and appearance. The authors envision that this approach would allow for application-specific algorithms to focus directly on regions of high OOA likelihood, which would (1) reduce the need for human intervention, and (2) reduce the propensity for false positives. Using the dual perspective, this technique would allow for algorithms to focus on regions of normal anatomy to ascertain image quality and adapt to image appearance characteristics.

Project description:Diabetic glomerular injury is a major complication of diabetes mellitus and is the leading cause of end stage renal disease (ESRD). Healthy podocytes are essential for glomerular function and health. Injury or loss of these cells results in increased proteinuria and kidney dysfunction and is a common finding in various glomerulopathies. Thus, mechanistic understanding of pathways that protect podocytes from damage are essential for development of future therapeutics. MicroRNA-146a (miR-146a) is a negative regulator of inflammation and is highly expressed in myeloid cells and podocytes. We previously reported that miR-146a levels are significantly reduced in the glomeruli of patients with diabetic nephropathy (DN). Here we report generation of mice with selective deletion of miR-146a in podocytes and use of these mice in models of glomerular injury. Induction of glomerular injury in C57BL/6 wildtype mice (WT) and podocyte-specific miR-146a knockout (Pod-miR146a-/-) animals via administration of low-dose lipopolysaccharide (LPS) or nephrotoxic serum (NTS) resulted in increased proteinuria in the knockout mice, suggesting that podocyte-expressed miR-146a protects these cells, and thus glomeruli, from damage. Furthermore, induction of hyperglycemia using streptozotocin (STZ) also resulted in an accelerated development of glomerulopathy and a rapid increase in proteinuria in the knockout animals, as compared to the WT animals, further confirming the protective role of podocyte-expressed miR-146a. We also confirmed that the direct miR-146a target, ErbB4, was significantly upregulated in the diseased glomeruli and erlotinib, an ErbB4 and EGFR inhibitor, reducedits upregulation and the proteinuria in treated animals. Primary miR146-/- podocytes from these animals also showed a basally upregulated TGFβ-Smad3 signaling in vitro. Taken together, this study shows that podocyte-specific miR-146a is imperative for protecting podocytes from glomerular damage, via modulation of ErbB4/EGFR, TGFβ, and linked downstream signaling.

Dataset Information

A Multi-layered Quantitative In Vivo Expression Atlas of the Podocyte Unravels Kidney Disease Candidate Genes.

Publications

A Multi-layered Quantitative In Vivo Expression Atlas of the Podocyte Unravels Kidney Disease Candidate Genes.

Similar Datasets

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