| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Laboratory of Dendritic Cell Biology, Division of Rheumatology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104; and
Medical College of Georgia, Augusta, GA 30912
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-
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Alliance for Lupus Research (to R.C. and S.G.) and the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (to R.C.).
2 Current address: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140.
3 Address correspondence and reprint requests to Dr. Roberto Caricchio, Section of Rheumatology, Temple University, 3322 North Broad Street, Room 205, Medical Office Building, Philadelphia, PA 19140. E-mail address: roc{at}temple.edu
4 Abbreviations used in this paper: GN, glomerulonephritis; 5-AIQ, 5-aminoisoquinolinone; BBS, borate-buffered saline; BM, bone marrow; BUN, blood urea nitrogen; Ct, cycle threshold; ER, estrogen receptor; GBM, glomerular basement membrane; NTN, nephrotoxic serum-induced nephritis; NTS, nephrotoxic serum; PAR, poly(ADP-ribose); PARP-1, PAR polymerase-1; ROS, reactive oxygen species; NZB, New Zealand Black; NZW, New Zealand White.
5 The online version of this article contains supplemental material.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
