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Sci Transl Med. 2019 Oct 2;11(512). pii: eaaw3639. doi: 10.1126/scitranslmed.aaw3639.

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

Author information

1
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
2
Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA 92093, USA.
3
Division of Nephrology, Department of Medicine, University of Sao Paulo, Sao Paulo 05403, Brazil.
4
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
5
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
6
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
7
Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA.
8
Departments of Urology and Pathology, New York University School of Medicine and Veterans Affairs, New York Harbor Healthcare System, Manhattan Campus, New York, NY 10010, USA.
9
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. telachka@iu.edu.
10
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

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.

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