Circulating Mitochondrial DAMPs Are Not Effective Inducers of Proteinuria and Kidney Injury in Rodents
Open accessAbstract
Mitochondria in eukaryotic cells are derived from bacteria in evolution. Like bacteria, mitochondria contain DNA with unmethylated CpG motifs and formyl peptides, both of which have recently been shown to be damage associated molecular patterns (DAMPs) and induce immune response and cell injury. Based on the facts that circulating mitochondrial DAMPs (mtDAMPs) are increased in the patients of trauma or burn injury who also have proteinuria, that mtDAMPs can activate immune cells which in turn secrete glomerular permeability factors, that renal intrinsic cells express a variety of DAMP receptors, and that mtDAMPs can directly increase endothelial cell permeability in vitro, we hypothesized that mtDAMPs may be novel circulating factors inducing proteinuria and kidney injury. We tested this hypothesis by directly injecting mtDAMPs into rodents and examining urinary protein and kidney histology. We prepared mtDAMP samples, including mitochondrial DNA (mtDNA) and mitochondrial debris (MTD), from rodent liver. In mice, injection of mtDNA for 20 μg/ml initial concentration in circulation (much higher than the clinical range), did not cause any renal manifestations. However, an increased dose leading to 45 μg/ml initial concentration in circulation resulted in a transient, slight increase in urinary albumin. In rats, MTD injection resulting in 450 μg/ml initial concentration of MTD protein in circulation, which was much higher than the clinical range, caused mild, transient proteinuria and lung lesions. Multiple injections of such large amount of either mtDNA or MTD into rodents on 3 consecutive days also failed in inducing proteinuria and kidney injury. In summary, clinical levels of circulating mtDAMPs do not induce proteinuria and clinically irrelevant high levels of mtDAMPs cause only a transient and slight increase in urinary protein in rodents, suggesting that circulating mtDAMPs may not be responsible for the proteinuria and kidney injury in patients with trauma, burn injury, and other diseases.
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Intravenous injection of mtDNA into mice failed to induce proteinuria and kidney damage.
“the intravenous injection of mtDNA into mice failed to induce proteinuria and kidney damage68”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [68]
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Cites
Circulating mitochondrial DAMPs cause inflammatory responses to injury
Zhang, Q., Raoof, M., Chen, Y., Sumi, Y., Sursal, T., Junger, W., Brohi, K., Itagaki, K., & Hauser, C. J. (2010) · Nature · doi:10.1038/nature08780 · Cited by 3,812 · see citing works
CpG motifs in bacterial DNA trigger direct B-cell activation
Krieg, A. M., Yi, A.-K., Matson, S., Waldschmidt, T. J., Bishop, G. A., Teasdale, R., Koretzky, G. A., & Klinman, D. M. (1995) · Nature · doi:10.1038/374546a0 · Cited by 3,508 · see citing works
A Conditionally Immortalized Human Podocyte Cell Line Demonstrating Nephrin and Podocin Expression
Saleem, M. A., O’Hare, M. J., Reiser, J., Coward, R. J., Inward, C. D., Farren, T., Xing, C. Y., Ni, L., Mathieson, P. W., & Mundel, P. H. (2002) · Journal of the American Society of Nephrology · doi:10.1681/asn.v133630 · Cited by 1,122 · see citing works
The Role of Inflammatory Cytokines in Diabetic Nephropathy
Navarro‐González, J. F., & Fernández, C. M. (2008) · Journal of the American Society of Nephrology · doi:10.1681/asn.2007091048 · Cited by 936 · see citing works
Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome
Iyer, S. S., Pulskens, W. P., Sadler, J. J., Butter, L. M., Teske, G. J., Ulland, T. K., Eisenbarth, S. C., Florquin, S., Flavell, R. A., Leemans, J. C., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908698106 · Cited by 691 · see citing works
Induction of B7-1 in podocytes is associated with nephrotic syndrome
Reiser, J., von Gersdorff, G., Loos, M., Oh, J. S., Asanuma, K., Giardino, L., Rastaldi, M. P., Calvaresi, N., Watanabe, H., Schwarz, K., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20402 · Cited by 589 · see citing works
Shock, L. S., Thakkar, P. V., Peterson, E. J., Moran, R. G., & Taylor, S. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012311108 · Cited by 555 · see citing works
Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses
Collins, L. V., Hajizadeh, S., Holme, E., Jonsson, I., & Tarkowski, A. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0703328 · Cited by 504 · see citing works
HMGB1 Contributes to Kidney Ischemia Reperfusion Injury
Wu, H., Ma, J., Wang, P., Corpuz, T. M., Panchapakesan, U., Wyburn, K., & Chadban, S. J. (2010) · Journal of the American Society of Nephrology · doi:10.1681/asn.2009101048 · Cited by 357 · see citing works
MITOCHONDRIAL DNA IS RELEASED BY SHOCK AND ACTIVATES NEUTROPHILS VIA P38 MAP KINASE
Zhang, Q., Itagaki, K., & Hauser, C. J. (2010) · Shock · doi:10.1097/shk.0b013e3181cd8c08 · Cited by 354 · see citing works
Podocyte-Selective Deletion of Dicer Induces Proteinuria and Glomerulosclerosis
Shi, S., Yu, L., Chiu, C., Sun, Y., Chen, J., Khitrov, G., Merkenschlager, M., Holzman, L. B., Zhang, W., Mundel, P., et al. (2008) · Journal of the American Society of Nephrology · doi:10.1681/asn.2008030312 · Cited by 349 · see citing works
Self-citationThe Inflammasomes in Kidney Disease
Anders, H., & Muruve, D. A. (2011) · Journal of the American Society of Nephrology · doi:10.1681/asn.2010080798 · Cited by 349 · see citing works
Simmons, J. D., Lee, Y.-L., Mulekar, S., Kuck, J. L., Brevard, S. B., Gonzalez, R. P., Gillespie, M. N., & Richards, W. O. (2013) · Annals of Surgery · doi:10.1097/sla.0b013e3182a4ea46 · Cited by 259 · see citing works
Pervasive CpG suppression in animal mitochondrial genomes
Cardon, L. R., Burge, C., Clayton, D. A., & Karlin, S. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.9.3799 · Cited by 238 · see citing works
Sun, S., Sursal, T., Adibnia, Y., Zhao, C., Zheng, Y. Z., Li, H., Otterbein, L. E., Hauser, C. J., & Itagaki, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059989 · Cited by 216 · see citing works
Overview of factors contributing to the pathophysiology of progressive renal disease
Schlöndorff, D. (2008) · Kidney International · doi:10.1038/ki.2008.351 · Cited by 158 · see citing works
Rapid isolation method of animal mitochondrial DNA by the alkaline lysis procedure
Tamura, K., & Aotsuka, T. (1988) · Biochemical Genetics · doi:10.1007/bf00553878 · Cited by 139 · see citing works
A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome
Shimada, M., Johnson, R., May, W. S., Lingegowda, V., Sood, P., Nakagawa, T., Van, Q. C., Dass, B., & Ejaz, A. A. (2009) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfp330 · Cited by 130 · see citing works
Mitochondrial DNA I. Preparation and properties of mitochondrial DNA from chick liver
Borst, P., Ruttenberg, G. J. C. M., & Kroon, A. M. (1967) · Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis · doi:10.1016/0005-2787(67)90697-1 · Cited by 122 · see citing works
Yamanouchi, S., Kudo, D., Yamada, M., Miyagawa, N., Furukawa, H., & Kushimoto, S. (2013) · Journal of Critical Care · doi:10.1016/j.jcrc.2013.05.006 · Cited by 119 · see citing works
Crouser, E. D., Shao, G., JULIAN, M. W., Macre, J. E., Shadel, G. S., Tridandapani, S., Huang, Q., & Wewers, M. D. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181a001ae · Cited by 108 · see citing works
Goulopoulou, S., Matsumoto, T., Bomfim, G. F., & Webb, R. C. (2012) · Clinical Science · doi:10.1042/cs20120130 · Cited by 107 · see citing works
Gu, X., Yao, Y., Wu, G., Lv, T., Luo, L., & Song, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072834 · Cited by 103 · see citing works
RAGE Mediates Podocyte Injury in Adriamycin-induced Glomerulosclerosis
Guo, J., Ananthakrishnan, R., Qu, W., Lu, Y., Reiniger, N., Zeng, S., Ma, W., Rosario, R., Yan, S. F., Ramasamy, R., et al. (2008) · Journal of the American Society of Nephrology · doi:10.1681/asn.2007101109 · Cited by 101 · see citing works
Self-citationPlasma Mitochondrial DNA Concentrations after Trauma
Lam, N. Y. L., Rainer, T. H., Chiu, R. W. K., Joynt, G. M., & Lo, Y. M. D. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2003.025783 · Cited by 97 · see citing works
Extracellular matrix molecules: endogenous danger signals as new drug targets in kidney diseases
Schaefer, L. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.11.007 · Cited by 85 · see citing works
THE ROLE OF INNATE IMMUNITY IN SEPTIC ACUTE KIDNEY INJURIES
Gonçalves, G. M., Zamboni, D. S., & Câmara, N. O. S. (2010) · Shock · doi:10.1097/shk.0b013e3181e7e69e · Cited by 78 · see citing works
Mitochondrial transcription factor A is a proinflammatory mediator in hemorrhagic shock
Wang, P. (2012) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2012.959 · Cited by 73 · see citing works
Little, J., Simtchouk, S., Schindler, S. M., Villanueva, E. B., Gill, N. J., Walker, D., Wolthers, K. R., & Klegeris, A. (2014) · Molecular and cellular neurosciences · doi:10.1016/j.mcn.2014.04.003 · Cited by 70 · see citing works
Ries, M., Schuster, P., Thomann, S., Donhauser, N., Vollmer, J., & Schmidt, B. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.0612278 · Cited by 61 · see citing works
Microalbuminuria—A Biomarker of Renal Microvascular Disease
Futrakul, N., Sridama, V., & Futrakul, P. (2009) · Renal Failure · doi:10.1080/08860220802595948 · Cited by 55 · see citing works
Heat Shock Protein 60 Is Released in Immune-Mediated Glomerulonephritis and Aggravates Disease
Lang, A., Benke, D., Eitner, F., Engel, D. R., Ehrlich, S., Breloer, M., Hamilton‐Williams, E. E., Specht, S., Hoerauf, A. M., Floege, J., et al. (2004) · Journal of the American Society of Nephrology · doi:10.1681/asn.2004040276 · Cited by 54 · see citing works
Smad2-Dependent Downregulation of miR-30 Is Required for TGF-β-Induced Apoptosis in Podocytes
Shi, S., Yu, L., Zhang, T., Qi, H., Xavier, S., Ju, W., & Böttinger, E. P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0075572 · Cited by 53 · see citing works
Self-citationGlomerular permeability and trauma: A correlation between microalbuminuria and Injury Severity Score
Gaudio, A. R. D., Spina, R., Filippo, A. D., & Feri, M. (1999) · Critical Care Medicine · doi:10.1097/00003246-199910000-00004 · Cited by 53 · see citing works
Role of Circulating Cell-free DNA Levels in Patients With Severe Preeclampsia and HELLP Syndrome
Miranda, M. L., Macher, H. C., Múñoz‐Hernández, R., Vallejo‐Vaz, A. J., Moreno‐Luna, R., Villar, J. R., Guerrero, J. M., & Stiefel, P. (2013) · American Journal of Hypertension · doi:10.1093/ajh/hpt187 · Cited by 41 · see citing works
Axelsson, J., Persson, I. M., Rippe, A., & Rippe, B. (2009) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00246.2009 · Cited by 32 · see citing works
Anders, H. (2007) · Kidney International · doi:10.1038/sj.ki.5002436 · Cited by 30 · see citing works
Gosling, P. J., & Sutcliffe, A. J. (1986) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456328602300610 · Cited by 28 · see citing works
What has the immune system got against the glomerular podocyte?
Mathieson, P. W. (2003) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2003.02236.x · Cited by 23 · see citing works
Isolation of intact nuclei of high purity from mouse liver
Nagata, T., Redman, R. S., & Lakshman, M. (2009) · Analytical Biochemistry · doi:10.1016/j.ab.2009.11.017 · Cited by 17 · see citing works
Shakespeare, P. G., Coombes, E. J., Hambleton, J., & Furness, D. (1981) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456328101800606 · Cited by 16 · see citing works
Plasma Nuclear DNA and Mitochondrial DNA as Prognostic Markers in Corrosive Injury Patients
Chou, C.-C., Fang, H.-Y., Chen, Y.-L., Wu, C.-Y., Siao, F.-Y., & Chou, M.-J. (2008) · Digestive Surgery · doi:10.1159/000152846 · Cited by 13 · see citing works
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Trumpff, C., Michelson, J., Lagranha, C. J., Taleon, V., Karan, K. R., Sturm, G., Lindqvist, D., Fernström, J., Moser, D., Kaufman, B. A., et al. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.04.002 · Cited by 181 · see citing works
Crosstalk between the heart and peripheral organs in heart failure
Jahng, J. W. S., Song, E., & Sweeney, G. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.20 · Cited by 103 · see citing works
Aswani, A. D., Manson, J., Itagaki, K., Chiazza, F., Collino, M., Wupeng, W. L., Chan, T. K., Wong, W. S. F., Hauser, C. J., Thiemermann, C., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00891 · Cited by 101 · see citing works
Hu, Q., Ren, J., Ren, H., Wu, J., Wu, X., Liu, S., Wang, G., Gu, G., Guo, K., & Li, J. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/8074936 · Cited by 82 · see citing works
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Eirin, A., Saad, A., Tang, H. J., Herrmann, S. M., Woollard, J. R., Lerman, A., Textor, S. C., & Lerman, L. O. (2016) · Hypertension · doi:10.1161/hypertensionaha.116.07849 · Cited by 80 · see citing works
Becker, Y., Loignon, R.-C., Julien, A.-S., Marcoux, G., Allaeys, I., Lévesque, T., Rollet-Labelle, E., Benk-Fortin, H., Cloutier, N., Melki, I., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-40900-3 · Cited by 75 · see citing works
Urinary Mitochondrial DNA Levels Identify Acute Kidney Injury in Surgical Critical Illness Patients
Hu, Q., Ren, J., Wu, J., Li, G., Wu, X., Liu, S., Wang, G., Gu, G., Ren, H., Hong, Z., et al. (2017) · Shock · doi:10.1097/shk.0000000000000830 · Cited by 56 · see citing works
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Mulay, S. R., Kumar, S. V. R., Lech, M., Desai, J., & Anders, H. (2016) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2016.03.004 · Cited by 51 · see citing works
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Xia, H., Bao, W., & Shi, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00122 · Cited by 40 · see citing works
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Zhang, W. Z., Rice, M. C., Hoffman, K. L., Oromendia, C., Barjaktarević, I., Wells, J. M., Hastie, A. T., Labaki, W. W., Cooper, C. B., Comellas, A. P., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.133984 · Cited by 40 · see citing works
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Cao, H., Wu, J., Luo, J., Chen, X., Yang, J., & Fang, L. (2019) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3131 · Cited by 37 · see citing works
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Zhang, J.-Z., Wang, J., Qu, W.-C., Wang, X.-W., Liu, Z., Ren, J.-X., Li, H., & Sun, T. (2017) · Injury · doi:10.1016/j.injury.2017.01.009 · Cited by 26 · see citing works
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Zajonz, T. S., Koch, C., Schwiddessen, J., Markmann, M., Hecker, M., Edinger, F., Schmidt, G., Boening, A., Sander, M., & Schneck, E. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11112994 · Cited by 11 · see citing works
Plotnikov, E. Y., Jankauskas, S. S., Zinovkin, R. A., Zorova, L. D., Zorov, S. D., Pevzner, I. B., Silachev, D. N., & Zorov, D. B. (2020) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-020-04853-2 · Cited by 8 · see citing works
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- Authors
- He, J., Lu, Y., Xia, H., Liang, Y., Wang, X., Bao, W., Yun, S., Ye, Y., Zheng, C., Liu, Z., & Shi, S.
- Affiliations
- Nanjing General Hospital of Nanjing Military Command (CN)
- Corresponding author
- Liu, Zhihong
- Shi, Shaolin
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-04-22
- Volume
- 10
- Issue
- 4
- Pages
- e0124469
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4406729
- OpenAlex
- W2085148213
- Cited by
- 20
- References
- 42
- Citations by year
- 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 1
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (30900686, 973 Program, 81370827, 2012CB517600)
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province (BK20131324, 2012CB517600)
- National Key Research and Development Program of China (2012CB517600, 2012CB517606)
- Topics
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mitochondrial DAMPs, damage-associated molecular patterns, mitochondrial DNA, proteinuria, kidney injury, glomerular permeability, endothelial permeability, trauma (physical injury), burns, urinary albumin, rodent models
- MeSH terms
- Animals, DNA, Mitochondrial, Kidney, Kidney Diseases, Kinetics, Liver, Lung, Mice, Inbred BALB C, Mitochondria, Neutrophils, Proteinuria, Rats, Sprague-Dawley
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