title: Circulating Mitochondrial DAMPs Are Not Effective Inducers of Proteinuria and Kidney Injury in Rodents.
abstract: 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.
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Yuqiu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xia
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Yaojun
authors.initials: Y
authors.lastname: Liang
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Wenduona
authors.initials: W
authors.lastname: Bao
authors.affiliation: Department of Comparative Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Yun
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Ye
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zheng
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Shaolin
authors.initials: S
authors.lastname: Shi
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000097:blood; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000150:complications* / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011507:Proteinuria / Q000097:blood / Q000150:complications* / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D004272:DNA, Mitochondrial