Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel

High serum concentrations of kidney-derived protein uromodulin [Tamm-Horsfall protein (THP)] have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generat...

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Published inScience translational medicine Vol. 11; no. 512
Main Authors LaFavers, Kaice A, Macedo, Etienne, Garimella, Pranav S, Lima, Camila, Khan, Shehnaz, Myslinski, Jered, McClintick, Jeanette, Witzmann, Frank A, Winfree, Seth, Phillips, Carrie L, Hato, Takashi, Dagher, Pierre C, Wu, Xue-Ru, El-Achkar, Tarek M, Micanovic, Radmila
Format Journal Article
LanguageEnglish
Published United States 02.10.2019
Subjects
Adult
Animals
Doxycycline - pharmacology
Female
HEK293 Cells
Humans
Male
Mice
Middle Aged
Oxidative Stress - drug effects
Reactive Oxygen Species - metabolism
Signal Transduction - drug effects
TRPM Cation Channels - genetics
TRPM Cation Channels - metabolism
Uromodulin - blood
Uromodulin - metabolism
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Summary:High serum concentrations of kidney-derived protein uromodulin [Tamm-Horsfall protein (THP)] have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with postsurgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity, and our findings might help explain how circulating THP deficiency is linked with poor outcomes and increased mortality.
ISSN:1946-6242
DOI:10.1126/scitranslmed.aaw3639