Identification of Biomarkers for PKD1 Using Urinary Exosomes

Hogan, Marie C.; Bakeberg, Jason L.; Gainullin, Vladimir G.; Irazabal, María V.; Harmon, Amber J.; Lieske, John C.; Charlesworth, M. Cristine; Johnson, Kenneth L.; Madden, Benjamin J.; Zenka, Roman M.; McCormick, Daniel J.; Sundsbak, Jamie L.; Heyer, Christina M.; Torres, Vicente E.; Harris, Peter C.; Ward, Christopher J.

doi:10.1681/asn.2014040354

Cited by 111 publications

(105 citation statements)

References 32 publications

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“…This suggests possible diseasespecific modifications. Recently, Hogan et al 92 showed that transmembrane protein-2 (TMEM2) in uEX was 2-fold higher in patients with PKD1 compared with controls. PC to TMEM ratio correlated inversely with kidney volume.…”

Section: Tubular Diseasementioning

confidence: 99%

Extracellular Vesicles in Renal Diseases

Erdbrügger

2016

Journal of the American Society of Nephrology

165

175

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Extracellular vesicles from the urine and circulation have gained significant interest as potential diagnostic biomarkers in renal diseases. Urinary extracellular vesicles contain proteins from all sections of the nephron, whereas most studied circulating extracellular vesicles are derived from platelets, immune cells, and the endothelium. In addition to their diagnostic role as markers of kidney and vascular damage, extracellular vesicles may have functional significance in renal health and disease by facilitating communication between cells and protecting against kidney injury and bacterial infection in the urinary tract. However, the current understanding of extracellular vesicles has derived mostly from studies with very small numbers of patients or in vitro data. Moreover, accurate assessment of these vesicles remains a challenge, in part because of a lack of consensus in the methodologies to measure extracellular vesicles and the inability of most techniques to capture the entire size range of these vesicles. However, newer techniques and standardized protocols to improve the detection of extracellular vesicles are in development. A clearer understanding of the composition and biology of extracellular vesicles will provide insights into their pathophysiologic, diagnostic, and therapeutic roles.

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Section: Tubular Diseasementioning

confidence: 99%

Extracellular Vesicles in Renal Diseases

Erdbrügger

2016

Journal of the American Society of Nephrology

165

175

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“…To determine whether the ΔL mutation affects PC1 intracellular membrane localization we analyzed protein from E14.5 whole embryo membrane preparations following fractionation over a heavy water/5–30% sucrose gradient (35) to separate membrane compartments. Immunoblot analysis of the total membrane preparations revealed comparable levels of full-length, and mature and immature NTF glycoforms of PC1 from WT and Pkd1 ΔL/ΔL embryos (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Membranes were clarified by gentle centrifugation, equilibrated and applied to a heavy water/5–30% sucrose gradient (35) and centrifuged at ∼274 000 g for 16 h in a Sorvall TH-641 rotor. Gradient fractions were collected from the top down using a BioComp fraction collector.…”

Section: Methodsmentioning

confidence: 99%

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD

Parnell

Magenheimer

Maser

et al. 2018

Human Molecular Genetics

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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of renal cysts that ultimately destroy kidney function. Mutations in the PKD1 and PKD2 genes cause ADPKD. Their protein products, polycystin-1 (PC1) and polycystin-2 (PC2) have been proposed to form a calcium-permeable receptor-channel complex; however the mechanisms by which they function are almost completely unknown. Most mutations in PKD1 are truncating loss-of-function mutations or affect protein biogenesis, trafficking or stability and reveal very little about the intrinsic biochemical properties or cellular functions of PC1. An ADPKD patient mutation (L4132Δ or ΔL), resulting in a single amino acid deletion in a putative G-protein binding region of the PC1 C-terminal cytosolic tail, was found to significantly decrease PC1-stimulated, G-protein-dependent signaling in transient transfection assays. Pkd1ΔL/ΔL mice were embryo-lethal suggesting that ΔL is a functionally null mutation. Kidney-specific Pkd1ΔL/cond mice were born but developed severe, postnatal cystic disease. PC1ΔL protein expression levels and maturation were comparable to those of wild type PC1, and PC1ΔL protein showed cell surface localization. Expression of PC1ΔL and PC2 complexes in transfected CHO cells failed to support PC2 channel activity, suggesting that the role of PC1 is to activate G-protein signaling to regulate the PC1/PC2 calcium channel.

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“…A tantalizing but untested possibility is that polycystin inactivation results in both abnormal ciliary EVs and abnormal ciliary signaling, resulting in severe pathology (scenerios shown in Figure 2C and 2D). The latter was previously demonstrated while the former only recently: EVs isolated from ADPKD patients display different proteins than unaffected individuals and hence the proposal that urinary exosomes contain biomarkers for ADPKD (Hogan et al, 2015). By removing the cilium in a Pkd1 or Pkd2 mutant, abnormal EV-cilia interactions and signaling are abrograted, thereby suppressing cystogenesis.…”

Section: Do Abnormal Cilia-ev Interactions Contribute To Ciliopathies?mentioning

confidence: 97%

Ciliary Extracellular Vesicles: Txt Msg Organelles

Wang

Barr

2016

Cell Mol Neurobiol

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Cilia are sensory organelles that protrude from cell surfaces to monitor the surrounding environment. In addition to its role as sensory receiver, the cilium also releases extracellular vesicles (EVs). The release of sub-micron sized EVs is a conserved form of intercellular communication used by all three kingdoms of life. These extracellular organelles play important roles in both short and long range signaling between donor and target cells and may coordinate systemic responses within an organism in normal and diseased states. EV shedding from ciliated cells and EV-cilia interactions are evolutionarily conserved phenomena, yet remarkably little is known about the relationship between the cilia and EVs and the fundamental biology of EVs. Studies in the model organisms Chlamydomonas and C. elegans have begun to shed light on ciliary EVs. Chlamydomonas EVs are shed from tips of flagella and are bioactive. C. elegans EVs are shed and released by ciliated sensory neurons in an intraflagellar transport (IFT)-dependent manner. C. elegans EVs play a role in modulating animal-to-animal communication, and this EV bioactivity is dependent on EV cargo content. Some ciliary pathologies, or ciliopathies, are associated with abnormal EV shedding or with abnormal cilia-EV interactions, suggest the cilium may be an important organelle as an EV donor or as an EV target. Until the past few decades, both cilia and EVs were ignored as vestigial or cellular junk. As research interest in these two organelles continues to gain momentum, we envision a new field of cell biology emerging. Here, we propose that the cilium is a dedicated organelle for EV biogenesis and EV reception. We will also discuss possible mechanisms by which EVs exert bioactivity and explain how what is learned in model organisms regarding EV biogenesis and function may provide insight to human ciliopathies.

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Identification of Biomarkers for PKD1 Using Urinary Exosomes

Cited by 111 publications

References 32 publications

Extracellular Vesicles in Renal Diseases

Extracellular Vesicles in Renal Diseases

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD

Ciliary Extracellular Vesicles: Txt Msg Organelles

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