Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel

Uromodulin inhibits systemic oxidative stress via TRPM2. 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. 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.