Multiple clinical studies have shown that
bardoxolone methyl, a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with
chronic kidney disease. However, whether an Nrf2 activator can protect tubules from
proteinuria-induced tubular damage via anti-inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of
Cancer Research-derived
glomerulonephritis (ICGN) mouse model of
nephrosis, we examined the effects of
dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable
bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice. The tubular epithelial cells of ICGN mice showed a decrease in the size and number of mitochondria, as well as the breakdown of the crista structure, whereas the number and ultrastructure of mitochondria were maintained by the dh404 treatment. To further determine the effect of dh404 on mitochondrial function, we used human proximal tubular cells in vitro. Stimulation with
albumin and
free fatty acid increased mitochondrial
reactive oxygen species (ROS). However, dh404 administration diminished mitochondrial ROS. Our data show that dh404 significantly reduced
proteinuria-induced tubular cell mitochondrial damage, suggesting that improved redox balance and mitochondrial function and suppression of
inflammation underlie the cytoprotective mechanism of Nrf2 activators, including
bardoxolone methyl, in
diabetic kidney disease.-Nagasu, H., Sogawa, Y., Kidokoro, K., Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., Kashihara, N.
Bardoxolone methyl analog attenuates
proteinuria-induced tubular damage by modulating mitochondrial function.