Abstract
Immune mediated nephropathy is one of the most serious manifestations of lupus and is characterized by severe inflammation and necrosis that, if untreated, eventually leads to renal failure. Although lupus has a higher incidence in women, both sexes can develop lupus glomerulonephritis; nephritis in men develops earlier and is more severe than in women. It is therefore important to understand the cellular and molecular mechanisms mediating nephritis in each sex. Previous work by our lab found that the absence or pharmacological inhibition of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme involved in DNA repair and necrotic cell death, affects only male mice and results in milder nephritis, with less in situ inflammation, and diminished incidence of necrotic lesions, allowing for higher survival rates. A second pathway mediating necrosis involves Receptor-Interacting Serine-Threonine Kinase 3 (RIPK3); in this study we sought to investigate the impact of RIPK3 on the development of lupus and nephritis in both sexes. To this end, we used two inducible murine models of lupus: chronic graft versus host disease (cGvHD) and pristane-induced lupus; and nephrotoxic serum (NTS)-induced nephritis as a model of immune mediated nephropathy. We found that the absence of RIPK3 has neither positive nor negative impact on the disease development or progression of lupus and nephritis in all three models, and in both male and female mice. We conclude that RIPK3 is dispensable for the pathogenesis of lupus and immune mediated nephropathy as to accelerate, worsen or ameliorate the disease.
Highlights
Immune mediated nephropathy is one of the most serious manifestations of lupus disease
This murine model of lupus is dependent on allogeneic T cell help and tests the activation of endogenous autoreactive B cells and their production of autoantibodies directed toward nuclear components [20], which are a hallmark of lupus disease and major players in the initiation of lupus nephritis [4]
Necrotic cell death plays a significant role in the pathogenesis of autoimmunity [31] and necrotic pathways mediated by poly (ADP-ribose) polymerase-1 (PARP1) and RIPK3 are among the best characterized [8]
Summary
Immune mediated nephropathy is one of the most serious manifestations of lupus disease. It is characterized by severe inflammation and necrosis, and despite therapy, often leads to renal failure [1, 2]. Deposition of immune complexes within the glomerular subendothelial space is a hallmark of Immune mediated nephropathy and is associated with inflammation, complement activation and complementinduced tissue damage within the kidney [4]. Immune cells infiltrating the kidney contribute to vasculature damage, especially within the glomerular capillary tufts. This vascular damage often leads to the accumulation of fibrin and/or platelet-fibrin microthrombi within the glomerular capillaries. Fibrin accumulation limits filtration across the glomerular basement membrane, creating an ischemic environment within the glomerulus and setting the stage for an energy-deprived environment, which is the prerequisite for the initiation of programmed necrosis [5, 6]
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