Research ArticleAutoimmunity

Kidney tissue hypoxia dictates T cell–mediated injury in murine lupus nephritis

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Science Translational Medicine  08 Apr 2020:
Vol. 12, Issue 538, eaay1620
DOI: 10.1126/scitranslmed.aay1620

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Hypoxic autoimmunity

Systemic lupus erythematosus causes severe damage in multiple organs, including the kidney leading to the development of nephritis. However, the mechanisms contributing to lupus nephritis are not completely understood. Now, Chen et al. used lupus-prone mice and showed that the hypoxic environment associated with renal tissue injury modulated the activity of infiltrating T cells, promoting their effector function to cause tissue damage. Reducing renal hypoxia by inhibiting the hypoxia-inducible factor–1 (HIF-1) reduced T cell infiltration and kidney injury in lupus-prone mice, suggesting that targeting HIF-1 might be effective for treating lupus nephritis.


The kidney is a frequent target of autoimmune injury, including in systemic lupus erythematosus; however, how immune cells adapt to kidney’s unique environment and contribute to tissue damage is unknown. We found that renal tissue, which normally has low oxygen tension, becomes more hypoxic in lupus nephritis. In the injured mouse tissue, renal-infiltrating CD4+ and CD8+ T cells express hypoxia-inducible factor–1 (HIF-1), which alters their cellular metabolism and prevents their apoptosis in hypoxia. HIF-1–dependent gene-regulated pathways were also up-regulated in renal-infiltrating T cells in human lupus nephritis. Perturbation of these environmental adaptations by selective HIF-1 blockade inhibited infiltrating T cells and reversed tissue hypoxia and injury in murine models of lupus. The results suggest that targeting HIF-1 might be effective for treating renal injury in autoimmune diseases.

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