Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel

Kaice A. LaFavers, Etienne Macedo, Pranav S. Garimella, Camila Lima, Shehnaz Khan, Jered Myslinski, Jeanette McClintick, Frank A. Witzmann, Seth Winfree, Carrie L. Phillips, Takashi Hato, Pierre C. Dagher, Xue Ru Wu, Tarek M. El-Achkar, Radmila Micanovic

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalScience translational medicine
Volume11
Issue number512
DOIs
StatePublished - Oct 2 2019

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Uromodulin
Oxidative Stress
Acute Kidney Injury
Protein Deficiency
Reactive Oxygen Species
Mortality
Transient Receptor Potential Channels
Kidney
Serum
Oxidants
Dialysis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

LaFavers, K. A., Macedo, E., Garimella, P. S., Lima, C., Khan, S., Myslinski, J., ... Micanovic, R. (2019). Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel. Science translational medicine, 11(512). https://doi.org/10.1126/scitranslmed.aaw3639

Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel. / 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.

In: Science translational medicine, Vol. 11, No. 512, 02.10.2019.

Research output: Contribution to journalArticle

LaFavers, KA, Macedo, E, Garimella, PS, Lima, C, Khan, S, Myslinski, J, McClintick, J, Witzmann, FA, Winfree, S, Phillips, CL, Hato, T, Dagher, PC, Wu, XR, El-Achkar, TM & Micanovic, R 2019, 'Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel', Science translational medicine, vol. 11, no. 512. https://doi.org/10.1126/scitranslmed.aaw3639
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. / Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel. In: Science translational medicine. 2019 ; Vol. 11, No. 512.
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