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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel

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LaFavers, Kaice A. [1] ; Macedo, Etienne [2] ; Garimella, Pranav S. [2] ; Lima, Camila [3] ; Khan, Shehnaz [1] ; Myslinski, Jered [1] ; McClintick, Jeanette [4] ; Witzmann, Frank A. [5] ; Winfree, Seth [5] ; Phillips, Carrie L. [6] ; Hato, Takashi [1] ; Dagher, Pierre C. [7, 5, 1] ; Wu, Xue-Ru [8, 9, 10] ; El-Achkar, Tarek M. [7, 5, 1, 11, 12] ; Micanovic, Radmila [1]
Total Authors: 15
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[1] Indiana Univ Sch Med, Div Nephrol, Dept Med, Indianapolis, IN 46202 - USA
[2] Univ Calif San Diego, Div Nephrol Hypertens, Dept Med, San Diego, CA 92093 - USA
[3] Univ Sao Paulo, Div Nephrol, Dept Med, BR-05403 Sao Paulo - Brazil
[4] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 - USA
[5] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 - USA
[6] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 - USA
[7] Richard L Roudebush VA Med Ctr, Indianapolis, IN 46202 - USA
[8] NYU, Dept Urol, Sch Med, New York, NY - USA
[9] NYU, Dept Pathol, Sch Med, New York, NY 10010 - USA
[10] New York Harbor Healthcare Syst, Vet Affairs, Manhattan Campus, New York, NY 10010 - USA
[11] Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 - USA
[12] Indiana Univ Sch Med, Div Nephrol, 950 W Walnut, R2 202, Indianapolis, IN 46202 - USA
Total Affiliations: 12
Document type: Journal article
Source: Science Translational Medicine; v. 11, n. 512 OCT 2 2019.
Web of Science Citations: 2

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. (AU)

FAPESP's process: 13/12710-2 - Diagnosis and application of biomarkers of acute renal injury in perioperative liver transplantation
Grantee:Etienne Maria Vasconcellos de Macedo
Support type: Regular Research Grants