Abstract
Cell death can be divided into the anti-inflammatory process of apoptosis and the pro-inflammatory process of necrosis. Necrosis, as apoptosis, is a regulated form of cell death, and Poly-(ADP-Ribose) Polymerase-1 (PARP-1) and Receptor-Interacting Protein (RIP) 1/3 are major mediators. We previously showed that absence or inhibition of PARP-1 protects mice from nephritis, however only the male mice. We therefore hypothesized that there is an inherent difference in the cell death program between the sexes. We show here that in an immune-mediated nephritis model, female mice show increased apoptosis compared to male mice. Treatment of the male mice with estrogens induced apoptosis to levels similar to that in female mice and inhibited necrosis. Although PARP-1 was activated in both male and female mice, PARP-1 inhibition reduced necrosis only in the male mice. We also show that deletion of RIP-3 did not have a sex bias. We demonstrate here that male and female mice are prone to different types of cell death. Our data also suggest that estrogens and PARP-1 are two of the mediators of the sex-bias in cell death. We therefore propose that targeting cell death based on sex will lead to tailored and better treatments for each gender.
Highlights
Several inflammatory diseases show differences in severity and outcome between the two sexes
We previously observed a sex bias in the activity of Poly-(ADP-Ribose) Polymerase-1 (PARP-1). To determine whether this bias was due to the activation of PARP-1 in only one sex, we determined PARP-1 activation in male and female mice during lupus nephritis
The NZW/BXSB F1 male mice spontaneously develop lupus, whereas the female mice develop similar disease severity when injected with Interferon alpha (IFNa)
Summary
PARP-1 is activated in both male and female mice during nephritis. We previously observed a sex bias in the activity of PARP-1. The kidney sections from male and female mice were stained for Poly (ADP-Ribose) Polymers (PARs) as a measure of PARP-1 activation. An advantage of the NTN model is that it allows to ‘bypass’ the upstream events during systemic autoimmunity that lead to loss of tolerance and generation of auto-antibodies.[26,27] recent evidence suggests that, irrespective of the upstream events leading to immune-mediated nephritis, the downstream mechanisms involved in renal tissue damage are similar.[26,27] NTN in PARP-1-deficient mice demonstrates that PARP-1 is responsible for the majority of poly (ADP-ribosyl)ation in the nephritic kidney, and PAR accumulation can be used as a measure of PARP-1 activation (Figure 1c).
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