Research ArticleKidney Disease

Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel

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Science Translational Medicine  02 Oct 2019:
Vol. 11, Issue 512, eaaw3639
DOI: 10.1126/scitranslmed.aaw3639

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The oxidative hypothesis

Elevated plasma concentration of the kidney-derived protein uromodulin (THP) has been associated with better kidney function and decreased mortality in patients with and without kidney diseases. However, causal relationship and underlying mechanisms remain unclear. Now, LaFavers et al. used transgenic mice and showed that THP deletion resulted in systemic oxidative damage induced by activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. In plasma samples from patients with kidney injury, THP was negatively correlated with ROS expression, and oxidative damage was associated with increased mortality. TRPM2 inhibition in a mouse model of kidney injury reduced the injury-mediated ROS increase.

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