Hypovitaminosis A Drives the Progression of Tubulointerstitial Lupus Nephritis through Potentiating Predisease Cellular Autoreactivity.
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Vitamin A (VA) deficiency (VAD) is observed in both humans and mice with lupus nephritis. However, whether VAD is a driving factor for accelerated progression of lupus nephritis is unclear. In this study, we investigated the effect of VAD on the progression of lupus nephritis in a lupus-prone mouse model, MRL/lpr. We initiated VAD either during gestation or after weaning to reveal a potential time-dependent effect. We found exacerbated lupus nephritis at 15 wk of age with both types of VAD that provoked tubulointerstitial nephritis leading to renal failure. This was concomitant with significantly higher mortality in all VAD mice. Importantly, restoration of VA levels after weaning reversed VAD-induced mortality. These results suggest VAD-driven acceleration of tubulointerstitial lupus nephritis. Mechanistically, at the earlier time point of 7 wk of age and before the onset of clinical lupus nephritis, continued VAD (from gestation until postweaning) enhanced plasma cell activation and augmented their autoantibody production, while also increasing the expansion of T lymphocytes that could promote plasma cell autoreactivity. Moreover, continued VAD increased the renal infiltration of plasmacytoid dendritic cells. VAD initiated after weaning, in contrast, showed modest effects on autoantibodies and renal plasmacytoid dendritic cells that were not statistically significant. Remarkably, analysis of gene expression in human kidney revealed that the retinoic acid pathway was decreased in the tubulointerstitial region of lupus nephritis, supporting our findings in MRL/lpr mice. Future studies will elucidate the underlying mechanisms of how VAD modulates cellular functions to exacerbate tubulointerstitial lupus nephritis.
Abdelhamid, L., Alajoleen, R., Kingsmore, K. M., Cabana-Puig, X., Lu, R., Zhu, J., ... Luo, X. M.
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Abdelhamid, Leila||Alajoleen, Razan||Kingsmore, Kathryn M||Cabana-Puig, Xavier||Lu, Ran||Zhu, Jing||Testerman, James C||Li, Yaqi||Ross, A Catharine||Cecere, Thomas E||Reilly, Christopher M||Grammer, Amrie C||Lipsky, Peter E||Luo, Xin M
