Poly(ADP-Ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation

Neelakshi R. Jog, Joudy Ann Dinnall, Stefania Gallucci, Michael P. Madaio, Roberto Caricchio

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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 17β-estradiol prolonged their survival during the course of nephritis. PARP-1 also regulated TNF-α 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.

Original languageEnglish (US)
Pages (from-to)7297-7306
Number of pages10
JournalJournal of Immunology
Volume182
Issue number11
DOIs
StatePublished - Jun 1 2009

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Nephritis
Cell Death
Inflammation
Glomerulonephritis
Kidney
Necrosis
Poly (ADP-Ribose) Polymerase-1
DNA Repair Enzymes
Glomerular Basement Membrane
Blood Urea Nitrogen
Disease Progression
Estradiol
Up-Regulation
Pharmacology

ASJC Scopus subject areas

  • Immunology

Cite this

Poly(ADP-Ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation. / Jog, Neelakshi R.; Dinnall, Joudy Ann; Gallucci, Stefania; Madaio, Michael P.; Caricchio, Roberto.

In: Journal of Immunology, Vol. 182, No. 11, 01.06.2009, p. 7297-7306.

Research output: Contribution to journalArticle

Jog, Neelakshi R. ; Dinnall, Joudy Ann ; Gallucci, Stefania ; Madaio, Michael P. ; Caricchio, Roberto. / Poly(ADP-Ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation. In: Journal of Immunology. 2009 ; Vol. 182, No. 11. pp. 7297-7306.
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