skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Glomerular filtrate proteins in acute cardiorenal syndrome

Abstract

Acute cardiorenal syndrome (CRS-1) is a morbid complication of acute cardiovascular disease. Heart-to-kidney signals transmitted by “cardiorenal connectors” have been postulated, but investigation into CRS-1 has been limited by technical limitations and a paucity of models. To address these limitations, we developed a translational model of CRS-1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR), and now report findings from nanoscale mass spectrometry proteomic exploration of glomerular filtrate 2 hours after CA/CPR or sham procedure. Filtrate acquisition was confirmed by imaging, molecular weight and charge distribution, and exclusion of protein specific to surrounding cells. Filtration of proteins specific to the heart was detected following CA/CPR and confirmed with mass spectrometry performed using urine collections from mice with deficient tubular endocytosis. Cardiac LIM protein was a CA/CPR-specific filtrate component. Cardiac arrest induced plasma release of cardiac LIM protein in mice and critically ill human cardiac arrest survivors, and administration of recombinant cardiac LIM protein to mice altered renal function. These findings demonstrate that glomerular filtrate is accessible to nanoscale proteomics and elucidate the population of proteins filtered 2 hours after CA/CPR. The identification of cardiac-specific proteins in renal filtrate suggests a novel signaling mechanism in CRS-1. We expect these findings to advance understandingmore » of CRS-1.« less

Authors:
ORCiD logo; ; ; ; ; ORCiD logo; ; ; ; ; ORCiD logo;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1507522
Report Number(s):
PNNL-SA-129539
Journal ID: ISSN 2379-3708
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
JCI Insight
Additional Journal Information:
Journal Volume: 4; Journal Issue: 4; Journal ID: ISSN 2379-3708
Publisher:
American Society for Clinical Investigation
Country of Publication:
United States
Language:
English

Citation Formats

Wakasaki, Rumie, Matsushita, Katsuyuki, Golgotiu, Kirsti, Anderson, Sharon, Eiwaz, Mahaba B., Orton, Daniel J., Han, Sang Jun, Lee, H. Thomas, Smith, Richard D., Rodland, Karin D., Piehowski, Paul D., and Hutchens, Michael P. Glomerular filtrate proteins in acute cardiorenal syndrome. United States: N. p., 2019. Web. doi:10.1172/jci.insight.122130.
Wakasaki, Rumie, Matsushita, Katsuyuki, Golgotiu, Kirsti, Anderson, Sharon, Eiwaz, Mahaba B., Orton, Daniel J., Han, Sang Jun, Lee, H. Thomas, Smith, Richard D., Rodland, Karin D., Piehowski, Paul D., & Hutchens, Michael P. Glomerular filtrate proteins in acute cardiorenal syndrome. United States. doi:10.1172/jci.insight.122130.
Wakasaki, Rumie, Matsushita, Katsuyuki, Golgotiu, Kirsti, Anderson, Sharon, Eiwaz, Mahaba B., Orton, Daniel J., Han, Sang Jun, Lee, H. Thomas, Smith, Richard D., Rodland, Karin D., Piehowski, Paul D., and Hutchens, Michael P. Thu . "Glomerular filtrate proteins in acute cardiorenal syndrome". United States. doi:10.1172/jci.insight.122130.
@article{osti_1507522,
title = {Glomerular filtrate proteins in acute cardiorenal syndrome},
author = {Wakasaki, Rumie and Matsushita, Katsuyuki and Golgotiu, Kirsti and Anderson, Sharon and Eiwaz, Mahaba B. and Orton, Daniel J. and Han, Sang Jun and Lee, H. Thomas and Smith, Richard D. and Rodland, Karin D. and Piehowski, Paul D. and Hutchens, Michael P.},
abstractNote = {Acute cardiorenal syndrome (CRS-1) is a morbid complication of acute cardiovascular disease. Heart-to-kidney signals transmitted by “cardiorenal connectors” have been postulated, but investigation into CRS-1 has been limited by technical limitations and a paucity of models. To address these limitations, we developed a translational model of CRS-1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR), and now report findings from nanoscale mass spectrometry proteomic exploration of glomerular filtrate 2 hours after CA/CPR or sham procedure. Filtrate acquisition was confirmed by imaging, molecular weight and charge distribution, and exclusion of protein specific to surrounding cells. Filtration of proteins specific to the heart was detected following CA/CPR and confirmed with mass spectrometry performed using urine collections from mice with deficient tubular endocytosis. Cardiac LIM protein was a CA/CPR-specific filtrate component. Cardiac arrest induced plasma release of cardiac LIM protein in mice and critically ill human cardiac arrest survivors, and administration of recombinant cardiac LIM protein to mice altered renal function. These findings demonstrate that glomerular filtrate is accessible to nanoscale proteomics and elucidate the population of proteins filtered 2 hours after CA/CPR. The identification of cardiac-specific proteins in renal filtrate suggests a novel signaling mechanism in CRS-1. We expect these findings to advance understanding of CRS-1.},
doi = {10.1172/jci.insight.122130},
journal = {JCI Insight},
issn = {2379-3708},
number = 4,
volume = 4,
place = {United States},
year = {2019},
month = {2}
}

Works referenced in this record:

Extracranial Hypothermia During Cardiac Arrest and Cardiopulmonary Resuscitation Is Neuroprotective In Vivo
journal, June 2014

  • Hutchens, Michael P.; Fujiyoshi, Tetsuhiro; Koerner, Ines P.
  • Therapeutic Hypothermia and Temperature Management, Vol. 4, Issue 2
  • DOI: 10.1089/ther.2014.0003

Disturbance in Z-Disk Mechanosensitive Proteins Induced by a Persistent Mutant Myopalladin Causes Familial Restrictive Cardiomyopathy
journal, December 2014

  • Huby, Anne-Cecile; Mendsaikhan, Uzmee; Takagi, Ken
  • Journal of the American College of Cardiology, Vol. 64, Issue 25
  • DOI: 10.1016/j.jacc.2014.09.071

Initial Quantitative Proteomic Map of 28 Mouse Tissues Using the SILAC Mouse
journal, February 2013

  • Geiger, Tamar; Velic, Ana; Macek, Boris
  • Molecular & Cellular Proteomics, Vol. 12, Issue 6
  • DOI: 10.1074/mcp.M112.024919

Cardiorenal syndrome—current understanding and future perspectives
journal, November 2013

  • Braam, Branko; Joles, Jaap A.; Danishwar, Amir H.
  • Nature Reviews Nephrology, Vol. 10, Issue 1
  • DOI: 10.1038/nrneph.2013.250

Estrogen-Mediated Renoprotection following Cardiac Arrest and Cardiopulmonary Resuscitation Is Robust to GPR30 Gene Deletion
journal, June 2014


Target organ cross talk in cardiorenal syndrome: animal models
journal, November 2012

  • Bongartz, Lennart G.; Braam, Branko; Gaillard, Carlo A.
  • American Journal of Physiology-Renal Physiology, Vol. 303, Issue 9
  • DOI: 10.1152/ajprenal.00392.2012

Mild renal ischemia-reperfusion reduces charge and size selectivity of the glomerular barrier
journal, June 2007

  • Andersson, Maria; Nilsson, Ulf; Hjalmarsson, Clara
  • American Journal of Physiology-Renal Physiology, Vol. 292, Issue 6
  • DOI: 10.1152/ajprenal.00152.2006

Evidence for the Role of Megalin in Renal Uptake of Transthyretin
journal, September 2000

  • Sousa, Mónica Mendes; Norden, Anthony G. W.; Jacobsen, Christian
  • Journal of Biological Chemistry, Vol. 275, Issue 49
  • DOI: 10.1074/jbc.M002886200

Cardiorenal Syndrome in Western Countries: Epidemiology, Diagnosis and Management Approaches
journal, January 2016

  • Ronco, Claudio; Di Lullo, Luca
  • Kidney Diseases, Vol. 2, Issue 4
  • DOI: 10.1159/000448749

Incidence, Mortality and Positive Predictive Value of Type 1 Cardiorenal Syndrome in Acute Coronary Syndrome
journal, December 2016

  • Pimienta González, Raquel; Couto Comba, Patricia; Rodríguez Esteban, Marcos
  • PLOS ONE, Vol. 11, Issue 12
  • DOI: 10.1371/journal.pone.0167166

Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect
journal, February 2003

  • Leheste, JÖRg R.; Melsen, Flemming; Wellner, Maren
  • The FASEB Journal, Vol. 17, Issue 2
  • DOI: 10.1096/fj.02-0578fje

Cubilin- and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney
journal, October 2000


Myocyte remodeling in response to hypertrophic stimuli requires nucleocytoplasmic shuttling of muscle LIM protein
journal, October 2009

  • Boateng, Samuel Y.; Senyo, Samuel E.; Qi, Lixin
  • Journal of Molecular and Cellular Cardiology, Vol. 47, Issue 4
  • DOI: 10.1016/j.yjmcc.2009.04.006

Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy
journal, May 2008

  • Geier, Christian; Gehmlich, Katja; Ehler, Elisabeth
  • Human Molecular Genetics, Vol. 17, Issue 18
  • DOI: 10.1093/hmg/ddn160

Proteomic mapping of proteins released during necrosis and apoptosis from cultured neonatal cardiac myocytes
journal, April 2014

  • Marshall, Kurt D.; Edwards, Michelle A.; Krenz, Maike
  • American Journal of Physiology-Cell Physiology, Vol. 306, Issue 7
  • DOI: 10.1152/ajpcell.00167.2013

The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: Retrieval is disrupted in nephrotic states
journal, March 2007

  • Russo, L. M.; Sandoval, R. M.; McKee, M.
  • Kidney International, Vol. 71, Issue 6
  • DOI: 10.1038/sj.ki.5002041

STEPS: A grid search methodology for optimized peptide identification filtering of MS/MS database search results
journal, February 2013

  • Piehowski, Paul D.; Petyuk, Vladislav A.; Sandoval, John D.
  • PROTEOMICS, Vol. 13, Issue 5
  • DOI: 10.1002/pmic.201200096

Accurate Proteome-wide Label-free Quantification by Delayed Normalization and Maximal Peptide Ratio Extraction, Termed MaxLFQ
journal, June 2014

  • Cox, Jürgen; Hein, Marco Y.; Luber, Christian A.
  • Molecular & Cellular Proteomics, Vol. 13, Issue 9
  • DOI: 10.1074/mcp.M113.031591

SNaPP: Simplified Nanoproteomics Platform for Reproducible Global Proteomic Analysis of Nanogram Protein Quantities
journal, March 2016

  • Huang, Eric L.; Piehowski, Paul D.; Orton, Daniel J.
  • Endocrinology, Vol. 157, Issue 3
  • DOI: 10.1210/en.2015-1821

Nature of glomerular capillary permeability changes following acute renal ischemia-reperfusion injury in rats
journal, December 2006

  • Rippe, Catarina; Rippe, Anna; Larsson, Anna
  • American Journal of Physiology-Renal Physiology, Vol. 291, Issue 6
  • DOI: 10.1152/ajprenal.00123.2006

Muscle LIM Protein: Master regulator of cardiac and skeletal muscle functions
journal, July 2015


Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment
journal, April 2011

  • Cox, Jürgen; Neuhauser, Nadin; Michalski, Annette
  • Journal of Proteome Research, Vol. 10, Issue 4
  • DOI: 10.1021/pr101065j

edgeR: a Bioconductor package for differential expression analysis of digital gene expression data
journal, November 2009


Spatially-Resolved Proteomics: Rapid Quantitative Analysis of Laser Capture Microdissected Alveolar Tissue Samples
journal, December 2016

  • Clair, Geremy; Piehowski, Paul D.; Nicola, Teodora
  • Scientific Reports, Vol. 6, Issue 1
  • DOI: 10.1038/srep39223

Kidney Proximal Tubular TLR9 Exacerbates Ischemic Acute Kidney Injury
journal, June 2018


Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy
journal, July 2016

  • Mori, Keita P.; Yokoi, Hideki; Kasahara, Masato
  • Journal of the American Society of Nephrology, Vol. 28, Issue 1
  • DOI: 10.1681/ASN.2015101168

An Endocytic Pathway Essential for Renal Uptake and Activation of the Steroid 25-(OH) Vitamin D3
journal, February 1999


Estrogen Is Renoprotective via a Nonreceptor-dependent Mechanism after Cardiac Arrest In Vivo
journal, January 2010


2016 update of the PRIDE database and its related tools
journal, November 2015

  • Vizcaíno, Juan Antonio; Csordas, Attila; del-Toro, Noemi
  • Nucleic Acids Research, Vol. 44, Issue D1
  • DOI: 10.1093/nar/gkv1145

Quantum dot–based multiphoton fluorescent pipettes for targeted neuronal electrophysiology
journal, October 2014

  • Andrásfalvy, Bertalan K.; Galiñanes, Gregorio L.; Huber, Daniel
  • Nature Methods, Vol. 11, Issue 12
  • DOI: 10.1038/nmeth.3146

Extended Multiplexing of Tandem Mass Tags (TMT) Labeling Reveals Age and High Fat Diet Specific Proteome Changes in Mouse Epididymal Adipose Tissue
journal, March 2017

  • Plubell, Deanna L.; Wilmarth, Phillip A.; Zhao, Yuqi
  • Molecular & Cellular Proteomics, Vol. 16, Issue 5
  • DOI: 10.1074/mcp.M116.065524

Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo
journal, August 2012

  • Hutchens, Michael P.; Fujiyoshi, Tetsuhiro; Komers, Radko
  • American Journal of Physiology-Renal Physiology, Vol. 303, Issue 3
  • DOI: 10.1152/ajprenal.00354.2011

Renal cortical albumin gene induction and urinary albumin excretion in response to acute kidney injury
journal, March 2011

  • Ware, Lorraine B.; Johnson, Ali C. M.; Zager, Richard A.
  • American Journal of Physiology-Renal Physiology, Vol. 300, Issue 3
  • DOI: 10.1152/ajprenal.00654.2010

Why Is Muscle Protein Synthesis, But Not Whole Body Protein Synthesis, Reduced in CRF Patients?
journal, January 2001

  • Veeneman, Jorden M.; de Jong, Paul E.; Huisman, Roel M.
  • American Journal of Physiology-Endocrinology and Metabolism, Vol. 280, Issue 1
  • DOI: 10.1152/ajpendo.2001.280.1.E197

Cardiac dysfunction and heart failure are associated with abnormalities in the subcellular distribution and amounts of oligomeric muscle LIM protein
journal, January 2007

  • Boateng, Samuel Y.; Belin, Rashad J.; Geenen, David L.
  • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 292, Issue 1
  • DOI: 10.1152/ajpheart.00766.2006

Determination of renal function and injury using near-infrared fluorimetry in experimental cardiorenal syndrome
journal, April 2017

  • Ikeda, Mizuko; Wakasaki, Rumie; Schenning, Katie J.
  • American Journal of Physiology-Renal Physiology, Vol. 312, Issue 4
  • DOI: 10.1152/ajprenal.00573.2016

Soluble Thrombomodulin Protects Ischemic Kidneys
journal, January 2009

  • Sharfuddin, Asif A.; Sandoval, Ruben M.; Berg, David T.
  • Journal of the American Society of Nephrology, Vol. 20, Issue 3
  • DOI: 10.1681/ASN.2008060593

Muscle LIM protein promotes myogenesis by enhancing the activity of MyoD.
journal, August 1997

  • Kong, Y.; Flick, M. J.; Kudla, A. J.
  • Molecular and Cellular Biology, Vol. 17, Issue 8
  • DOI: 10.1128/MCB.17.8.4750

Megalin Knockout Mice as an Animal Model of Low Molecular Weight Proteinuria
journal, October 1999


Reliability of Transcutaneous Measurement of Renal Function in Various Strains of Conscious Mice
journal, August 2013


Micropuncture studies of proximal tubule albumin concentrations in normal and nephrotic rats
journal, July 1971

  • Oken, Donald E.; Flamenbaum, Walter
  • Journal of Clinical Investigation, Vol. 50, Issue 7
  • DOI: 10.1172/JCI106635

Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study
journal, June 2009


Acute Kidney Injury in Cardiorenal Syndrome Type 1 Patients: A Systematic Review and Meta-Analysis
journal, December 2015

  • Vandenberghe, Wim; Gevaert, Sofie; Kellum, John A.
  • Cardiorenal Medicine, Vol. 6, Issue 2
  • DOI: 10.1159/000442300

MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes.
journal, October 1990

  • Choi, J.; Costa, M. L.; Mermelstein, C. S.
  • Proceedings of the National Academy of Sciences, Vol. 87, Issue 20
  • DOI: 10.1073/pnas.87.20.7988

Spectral Probabilities and Generating Functions of Tandem Mass Spectra: A Strike against Decoy Databases
journal, August 2008

  • Kim, Sangtae; Gupta, Nitin; Pevzner, Pavel A.
  • Journal of Proteome Research, Vol. 7, Issue 8
  • DOI: 10.1021/pr8001244

bioDBnet: the biological database network
journal, January 2009


Abrogation of Protein Uptake through Megalin-Deficient Proximal Tubules Does Not Safeguard against Tubulointerstitial Injury
journal, April 2007

  • Theilig, Franziska; Kriz, Wilhelm; Jerichow, Timo
  • Journal of the American Society of Nephrology, Vol. 18, Issue 6
  • DOI: 10.1681/ASN.2006111266

A High-Confidence Human Plasma Proteome Reference Set with Estimated Concentrations in PeptideAtlas
journal, June 2011

  • Farrah, Terry; Deutsch, Eric W.; Omenn, Gilbert S.
  • Molecular & Cellular Proteomics, Vol. 10, Issue 9
  • DOI: 10.1074/mcp.M110.006353

MS-GF+ makes progress towards a universal database search tool for proteomics
journal, October 2014

  • Kim, Sangtae; Pevzner, Pavel A.
  • Nature Communications, Vol. 5, Issue 1
  • DOI: 10.1038/ncomms6277

Albumin Is Recycled from the Primary Urine by Tubular Transcytosis
journal, August 2013

  • Tenten, Verena; Menzel, Sylvia; Kunter, Uta
  • Journal of the American Society of Nephrology, Vol. 24, Issue 12
  • DOI: 10.1681/ASN.2013010018

Release of Tissue-specific Proteins into Coronary Perfusate as a Model for Biomarker Discovery in Myocardial Ischemia/Reperfusion Injury
journal, March 2012

  • Cordwell, Stuart J.; Edwards, Alistair V. G.; Liddy, Kiersten A.
  • Journal of Proteome Research, Vol. 11, Issue 4
  • DOI: 10.1021/pr2006928

Micropuncture of Bowman's Space in Mice Facilitated by 2 Photon Microscopy
journal, January 2018

  • Matsushita, Katsuyuki; Golgotiu, Kirsti; Orton, Daniel J.
  • Journal of Visualized Experiments, Issue 140
  • DOI: 10.3791/58206