Global Analysis Reveals the Complexity of the Human Glomerular Extracellular Matrix

Lennon, Rachel; Byron, Adam; Humphries, Jonathan D.; Randles, Michael J.; Carisey, Alexandre F.; Murphy, Stephanie T.; Knight, David; Brenchley, Paul; Zent, Roy

doi:10.1681/asn.2013030233

Cited by 169 publications

(234 citation statements)

References 45 publications

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“…These findings are very similar to the tissue-derived glomerular ECM interactome, which identified a core of highly connected structural components. 15 Overall, these data suggest that qualitative differences between GEnC and podocyte ECMs do not affect the core organization of the ECM.…”

Section: Glomerular Cells In Vitro Exhibit Differential Ecm Protein Smentioning

confidence: 73%

“…There was considerable (55%) overlap between proteins detected in GEnC and podocyte ECMs, suggesting a common core of ECM proteins, but cell typespecific proteins were also identified ( Figure 2B). Furthermore, 44% of proteins in the recently described in vivo glomerular ECM proteome 15 were identified in cell-derived ECMs ( Figure 2B). Statistical analysis of all identified proteins in the cell-derived ECM samples revealed differential ECM protein synthesis between GEnCs and podocytes ( Figure 2C, Supplemental Table 3).…”

Section: Glomerular Cells In Vitro Exhibit Differential Ecm Protein Smentioning

confidence: 81%

“…15 To extend this global analysis, we analyzed cell-derived ECM from GEnCs and podocytes to determine their relative contribution to ECM production and regulation in the glomerulus.…”

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confidence: 99%

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Glomerular Cell Cross-Talk Influences Composition and Assembly of Extracellular Matrix

Byron

Randles

Humphries

et al. 2014

Journal of the American Society of Nephrology

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The glomerular basement membrane (GBM) is a specialized extracellular matrix (ECM) compartment within the glomerulus that contains tissue-restricted isoforms of collagen IV and laminin. It is integral to the capillary wall and therefore, functionally linked to glomerular filtration. Although the composition of the GBM has been investigated with global and candidate-based approaches, the relative contributions of glomerular cell types to the production of ECM are not well understood. To characterize specific cellular contributions to the GBM, we used mass spectrometry-based proteomics to analyze ECM isolated from podocytes and glomerular endothelial cells in vitro. These analyses identified cell type-specific differences in ECM composition, indicating distinct contributions to glomerular ECM assembly. Coculture of podocytes and endothelial cells resulted in an altered composition and organization of ECM compared with monoculture ECMs, and electron microscopy revealed basement membrane-like ECM deposition between cocultured cells, suggesting the involvement of cell-cell cross-talk in the production of glomerular ECM. Notably, compared with monoculture ECM proteomes, the coculture ECM proteome better resembled a tissue-derived glomerular ECM dataset, indicating its relevance to GBM in vivo. Protein network analyses revealed a common core of 35 highly connected structural ECM proteins that may be important for glomerular ECM assembly. Overall, these findings show the complexity of the glomerular ECM and suggest that both ECM composition and organization are context-dependent.

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Section: Glomerular Cells In Vitro Exhibit Differential Ecm Protein Smentioning

confidence: 73%

Section: Glomerular Cells In Vitro Exhibit Differential Ecm Protein Smentioning

confidence: 81%

See 1 more Smart Citation

Glomerular Cell Cross-Talk Influences Composition and Assembly of Extracellular Matrix

Byron

Randles

Humphries

et al. 2014

Journal of the American Society of Nephrology

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“…Nothing is known about such mechanisms in the kidney allograft. In glomeruli, global analyses of ECM has suggested this structure to be more complex than anticipated (96,351).…”

Section: Extracellular Matrixmentioning

confidence: 99%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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“…miR-378a-3p was described to target nephronectin (NPNT) in osteoblasts [19]. Mass spectrometry-based proteomics of extracellular glomerular matrix extracts in humans identified that NPNT expression is specifically localized in the GBM [20]. NPNT also is a ligand of integrin a8-b1 during kidney development [21][22][23].…”

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confidence: 99%

The Zebrafish Model to Study the Role of microRNAs in Glomerular Function and Disease

Müller-Deile¹,

Schiffer²

2017

Adv Tech Biol Med

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The zebrafish physiology of many organs including the kidney is very similar to that of human beings. Zebrafish develop from a fertilized egg to free-swimming larvae in only 48 h. The zebrafish larvae's correlate for the human kidney is the pronephros consisting of two nephrons with glomeruli fused at the embryo mid-line ventral to the dorsal aorta [1] ( Figure 1a).The glomerular filtration barrier of the pronephros is ultrastructurally almost indistinguishable from a mammalian glomerulus with interdigitating podocyte foot processes, a thin glomerular basement membrane and a fenestrated glomerular endothelium [2]. These structures can be found in 120 h old zebrafish larvae on ultrastructural level (Figures 1b and 1c). To generate these pictures zebrafish larvae were fixed in solution D and embedded in EPON. Ultrathin sectioning from head to tail was performed with a microtome until the glomerular region was found and sections transferred onto copper slit grids that were stained with uranyl acetate and lead citrate. Imaging was done with a transmission electron microscope.The pronephros tubular epithelium is composed of two proximal tubule segments, a proximal straight tubule as well as the early and late distal tubus [3]. The tubular system expresses a brush border of microvilli on the apical side for reabsorption processes (Figure 1d). The glomerular filtration of the zebrafish pronephros begins around 48 h post fertilization (hpf) [4]. Taking into consideration the structural and functional similarities and the fact that zebrafish gene expression can easily be influenced by specific knockdown and overexpression techniques using microinjections of morpholinos (MOs), mRNAs, microRNAs (miRs), small RNAs or CRISPR/Cas9 technology, the zebrafish serves as an ideal model to study glomerular diseases [5]. We and others successfully used the zebrafish model to screen for novel genes involved in kidney diseases [6][7][8]. On the other hand, gene mutations identified from human genetic studies can be verified as causative factors of proteinuric kidney disease in the zebrafish model. An upcoming field of research interest is the role of miRs in disease processes. MiRs regulate gene expression posttranscriptional by binding to the 3'-untranslated region (3' UTR) of a target mRNA and inhibiting translation [9,10]. Different miRs have been found to be enriched in human kidneys include miR-192, miR-194, miR-204, miR-215 and miR-216 [11]. MiRs are also essential for podocyte homeostasis [12][13][14][15] and can be secreted in body fluids [16,17].To antagonize the function of miRs, several antagomirs have been engineered and are commercially available. On the contrary, miR effects can be enhanced with miR mimics, which are chemically modified short double-stranded RNA sequences.Delivery of miRs in the zebrafish larvae system can be accomplished by microinjection of miR mimics in one-to-four cell stage or at 48 hpf by cardinal vein (c.v.) injection. After injections in egg stage the miR mimic is equally distributed in all zebra...

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Global Analysis Reveals the Complexity of the Human Glomerular Extracellular Matrix

Cited by 169 publications

References 45 publications

Glomerular Cell Cross-Talk Influences Composition and Assembly of Extracellular Matrix

Glomerular Cell Cross-Talk Influences Composition and Assembly of Extracellular Matrix

Renal Allograft Fibrosis: Biology and Therapeutic Targets

The Zebrafish Model to Study the Role of microRNAs in Glomerular Function and Disease

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