Methylglyoxal engages aging-associated mechanisms to cause filtration impairment in nephrocytes

The decline of glomerular filtration is a hallmark of aging. Methylglyoxal (MG) is a uremic toxin known to induce aging-like changes; however, whether its mechanism of action is similar remains unclear. We compare the underlying mechanisms of MG and aging using Drosophila nephrocytes as a model. In addition to lower body weight, reduced locomotion, and shorter lifespans, MG caused filtration defects and induced cellular senescence in nephrocytes similar to the effects of aging, with a corresponding upregulation of the LXR/RXR signaling pathway. Mechanistically, we found that MG and aging both increased reactive oxygen species (ROS). Antioxidant treatments and inhibition of the LXR/RXR pathway both improved the filtration function. In addition, MG and aging both reduced the level of Jub, which is a protein essential for the integrity of the slit diaphragm structure. Overexpressing jub enhanced slit diaphragm structure and prevented MG-induced functional decline. Together, the findings reveal parallel features between MG and aging, and show that inhibiting LXR/RXR signaling, reducing ROS, or strengthening the slit diaphragm structure can preserve the filtration function of Drosophila nephrocytes.