title: Mice lacking the 110-kD isoform of poly(ADP-ribose) glycohydrolase are protected against renal ischemia/reperfusion injury.
abstract: The role of poly(ADP-ribose) (PAR) glycohydrolase (PARG) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Poly(ADP-ribosyl)ation is rapidly stimulated in cells after DNA damage caused by the generation of reactive oxygen and nitrogen species during I/R. Continuous or excessive activation of poly(ADP-ribose) polymerase-1 produces extended chains of ADP-ribose on nuclear proteins and results in a substantial depletion of intracellular NAD(+) and subsequently, ATP, leading to cellular dysfunction and, ultimately, cell death. The key enzyme involved in polymer turnover is PARG, which possesses mainly exoglycosidase activity but can remove olig(ADP-ribose) fragments via endoglycosidic cleavage. Thus, the aim of this study was to investigate whether the absence of PARG(110) reduced the renal dysfunction, injury, and inflammation caused by I/R of the mouse kidney. Here, the renal dysfunction and injury caused by I/R (bilateral renal artery occlusion [30 min] followed by reperfusion [24 h]) in mice lacking PARG(110), the major nuclear isoform of PARG, was investigated. The following markers of renal dysfunction and injury were measured: Plasma urea, creatinine, aspartate aminotransferase, and histology. The following markers of inflammation were also measured: Myeloperoxidase activity, malondialdehyde levels, and plasma nitrite/nitrate. The degree of renal injury and dysfunction caused by I/R was significantly reduced in PARG(110)-deficient mice when compared with their wild-type littermates, and there were no differences in any of the biochemical parameters measured between sham-operated PARG(110)(-/-) mice and sham-operated wild-type littermates. Thus, it is proposed that endogenous PARG(110) plays a pivotal role in the pathophysiology of I/R injury of the kidney.
authors.affiliation: Centre for Experimental Medicine, Nephrology & Critical Care, William Harvey Research Institute, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Cortes
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Poala
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Helder
authors.initials: H
authors.lastname: Mota-Filipe
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003404:Creatinine / Q000097:blood; D006026:Glycoside Hydrolases / Q000235:genetics* / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009393:Nephritis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D014508:Urea / Q000097:blood
chemical_list: D007527:Isoenzymes; D009566:Nitrates; D009573:Nitrites; D014508:Urea; D003404:Creatinine; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase