title: Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation.
abstract: Necrotic lesions and necrotic cell death characterize severe autoimmune nephritides, and contribute to local inflammation and to progression of the disease. Poly(ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme, is involved in the induction of necrosis and is a key player in the acute and chronic inflammation. Therefore, we hypothesized that PARP-1 controls the severity of nephritis by mediating the induction of necrosis in the kidney. We used lupus and anti-glomerular basement membrane models of nephritis to determine the effects of PARP-1 on the inflammatory response in the kidney. We show in this study that PARP-1 is indeed activated during the course of glomerulonephritis. We also show that the absence of PARP-1 or its pharmacological inhibition results in milder nephritis, with lower blood urea nitrogen levels, reduced necrotic lesions, and higher survival rates. The relevance of PARP-1 showed a strong male sex specificity, and treatment of male mice with 17beta-estradiol prolonged their survival during the course of nephritis. PARP-1 also regulated TNF-alpha expression and up-regulation of adhesion molecules, further supporting a role of PARP-1 in the inflammatory process within the kidney. Our results demonstrate that PARP-1 activation and consequent necrotic cell death play an important role in the pathogenesis of male nephritis, and suggest that PARP-1 can be a novel therapeutic target in glomerulonephritis.
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Neelakshi R
authors.initials: NR
authors.lastname: Jog
authors.forename: Joudy-Ann
authors.initials: JA
authors.lastname: Dinnall
authors.forename: Stefania
authors.initials: S
authors.lastname: Gallucci
authors.forename: Michael P
authors.initials: MP
authors.lastname: Madaio
authors.forename: Roberto
authors.initials: R
authors.lastname: Caricchio
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology; D018450:Disease Progression; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005921:Glomerulonephritis / Q000473:pathology*; D007249:Inflammation / Q000473:pathology*; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D009336:Necrosis / Q000209:etiology*; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000502:physiology*; D012737:Sex Factors; D015996:Survival Rate
chemical_list: D004958:Estradiol; D011065:Poly(ADP-ribose) Polymerases