Lupus nephritis develops in a RIP3-independent manner for both males and females (BA4P.136)

Abstract

Abstract Lupus nephritis is one of the most serious manifestations of lupus and is characterized by severe inflammation and necrosis, and if untreated leads to renal failure. Although lupus occurs more often in women, both sexes develop glomerulonephritis, which in males develops earlier and is more severe than in females. Previous work by our lab found that loss of Poly [ADP-ribose] polymerase 1 (PARP-1) activity, an enzyme involved in DNA repair and necrotic cell death, resulted in milder nephritis and higher survival rates among males only. A second necrotic pathway involves Receptor-Interacting Serine-Threonine Kinase 3 (RIP3), hence in this study we aimed to investigate the impact of RIP3 on nephritis and determine if this pathway is relevant in both sexes. To this end we used three inducible murine models of lupus nephritis: nephrotoxic serum (NTS)-induced nephritis, pristane-induced lupus and chronic graft versus host (cGVH) disease. We found that absence of RIP3 imparts no positive or negative effects on the development of lupus nephritis in all three models and in both male and female mice. In addition, in vivo experiments done in absence of both RIP3 and PARP-1 did not result in any additive effects between the two pathways, conferring protection only when PARP-1 was absent. Based on these studies, we conclude that RIP3 does not appear to play a significant role in lupus nephritis, nor does it appear to interact with PARP-1 to accelerate, worsen or ameliorate the disease.