Expression pattern of the deoxyribonuclease 1 gene: lessons from the Dnase1 knockout mouse

Napirei, Markus; Ricken, Albert; Eulitz, Dirk; Knoop, Heiko; Mannherz, Hans Georg

doi:10.1042/bj20040046

Cited by 90 publications

(85 citation statements)

References 43 publications

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“…19 Serum Dnase1 activity was quantified using the single radial enzyme diffusion assay and the native polyacrylamide gel electrophoresis zymogram technique as previously described. 11,12 Immunoblotting. Immunoblotting was performed on liver homogenates prepared as described above for quantitative DNA fragmentation assay.…”

Section: Methodsmentioning

confidence: 99%

“…9,10 DNASE1 gene expression has been demonstrated in a number of different organs of the urogenital and alimentary tracts as well as in the murine liver. 11 In a previous report, we showed that Dnase1 deficiency in the mouse promotes anti-DNA autoimmunity, suggesting a protective role of Dnase1 through its ability to degrade chromatin presumably liberated during cell death. 12 In addition, we have demonstrated that extracellular DNASE1 diffuses into necrotic cells, and together with the plasminogen system facilitates necrotic chromatin breakdown in vitro.…”

mentioning

confidence: 99%

“…9,10 DNASE1 gene expression has been demonstrated in a number of different organs of the urogenital and alimentary tracts as well as in the murine liver. 11 In a …”

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confidence: 99%

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Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

et al. 2006

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An overdose of acetaminophen (APAP) (N-acetyl-p-aminophenol) leads to hepatocellular necrosis induced by its metabolite N-acetyl-p-benzoquinone-imine, which is generated during the metabolic phase of liver intoxication. It has been reported that DNA damage occurs during the toxic phase; however, the nucleases responsible for this effect are unknown. In this study, we analyzed the participation of the hepatic endonuclease deoxyribonuclease 1 (DNASE1) during APAP-induced hepatotoxicity by employing a Dnase1 knockout (KO) mouse model. Male CD-1 Dnase1 wild-type (WT) (Dnase1 ؉/؉ ) and KO (Dnase1 ؊/؊ ) mice were treated with 2 different doses of APAP. Hepatic histopathology was performed, and biochemical parameters for APAP metabolism and necrosis were investigated, including depletion of glutathione/glutathione-disulfide (GSH؉GSSG), ␤-nicotinamide adenine dinucleotide (NADH؉NAD ؉ ), and adenosine triphosphate (ATP); release of aminotransferases and Dnase1; and occurrence of DNA fragmentation. As expected, an APAP overdose in WT mice led to massive hepatocellular necrosis characterized by the release of aminotransferases and depletion of hepatocellular GSH؉GSSG, NADH؉NAD ؉ , and ATP. These metabolic events were accompanied by extensive DNA degradation. In contrast, Dnase1 KO mice were considerably less affected. In conclusion, whereas the innermost pericentral hepatocytes of both mouse strains underwent necrosis to the same extent independent of DNA damage, the progression of necrosis to more outwardly located cells was dependent on DNA damage and only occurred in WT mice. Dnase1 aggravates APAP-induced liver necrosis. A cetaminophen, a widely used analgesic, is one of the most commonly overdosed pharmaceuticals. 1 Overdose leads to liver necrosis caused by the electrophilic metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which is generated via oxidation of acetaminophen (APAP) by a microsomal cytochrome P450 containing mixed-function oxidase system. 2 Subsequent detoxication of NAPQI by cellular glutathione leads to depletion of glutathione/glutathione-disulfide (GSHϩGSSG) followed by NAPQI accumulation and induction of necrosis due to protein arylation and severe oxidative stress. 2,3 Nuclear accumulation of Ca 2ϩ and DNA damage have been described to occur during APAPinduced cytotoxicity of murine hepatocytes in vitro and in vivo. 4-6 DNA damage seems to be an important event, because APAP toxicity was prevented by known inhibitors of Ca 2ϩ -dependent endonucleases, including Ca 2ϩ -chelators such as aurintricarboxylic acid, glycol ether diamine tetra-acetic acid, and the Ca 2ϩ -calmodulin antagonist chlorpromazine. 5,7,8 However, the nucleases involved in APAP-induced DNA damage have not yet been identified.Deoxyribonuclease 1 (DNASE1), a Ca 2ϩ /Mg 2ϩ -dependent secreted endonuclease with a pH optimum of approximately 7.5, hydrolyzes double-stranded DNA generating 5Ј-phospho-tri-and/or tetra-oligonucleotides. 9,10 DNASE1 gene expression has been demonstrated in a number of different organs of the urogenital and ...

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Section: Methodsmentioning

confidence: 99%

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Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

et al. 2006

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“…In the kidney, DNase I is highly expressed (18,40). We showed recently that among other endonucleases, EndoG and DNase II are also highly expressed in the kidney, whereas the expression of caspase-activated DNase and DNase ␥ is very low (17).…”

Section: Discussionmentioning

confidence: 99%

Cisplatin Nephrotoxicity Is Mediated by Deoxyribonuclease I

Basnakian

Apostolov

Yin

et al. 2005

Journal of the American Society of Nephrology

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108

106

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Cisplatin is commonly used for chemotherapy in a wide variety of tumors; however, its use is limited by kidney toxicity. Although the exact mechanism of cisplatin-induced nephrotoxicity is not understood, several studies showed that it is associated with DNA fragmentation induced by an unknown endonuclease. It was demonstrated previously that deoxyribonuclease I (DNase I) is a highly active renal endonuclease, and its silencing by antisense is cytoprotective against the in vitro hypoxia injury of kidney tubular epithelial cells. This study used recently developed DNase1 knockout (KO) mice to determine the role of this endonuclease in cisplatin-induced nephrotoxicity. The data showed that DNase I represents approximately 80% of the total endonuclease activity in the kidney and cultured primary renal tubular epithelial cells. In vitro, primary renal tubular epithelial cells isolated from KO animals were resistant to cisplatin (8 M) injury. DNase I KO mice were also markedly protected against the toxic injury induced by a single injection of cisplatin (20 mg/kg), by both functional (blood urea nitrogen and serum creatinine) and histologic criteria (tubular necrosis and in situ DNA fragmentation assessed by the terminal deoxynucleotidyl transferase nick end-labeling). These data provide direct evidence that DNase I is essential for kidney injury induced by cisplatin.

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“…However the actual role of the cytotoxic endonucleases was clarified much later. Cytotoxic endonucleases were found in all studied cells and tissues, including the prostate (Koizumi, 1995;Napirei et al, 2004). The enzymes belong to the family of hydrolyses that cleave phosphodiether bonds in DNA.…”

Section: Cytotoxic Endonucleases In Normal Prostate and Prostate Cancmentioning

confidence: 99%

Cytotoxic Endonucleases: New Targets for Prostate Cancer Chemotherapy

Wang¹,

Mikhailova²,

Basnakian³

2011

Prostate Cancer - From Bench to Bedside

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Expression pattern of the deoxyribonuclease 1 gene: lessons from the Dnase1 knockout mouse

Cited by 90 publications

References 43 publications

Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

Cisplatin Nephrotoxicity Is Mediated by Deoxyribonuclease I

Cytotoxic Endonucleases: New Targets for Prostate Cancer Chemotherapy

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