TY - JOUR
T1 - Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function
AU - Nagasu, Hajime
AU - Sogawa, Yuji
AU - Kidokoro, Kengo
AU - Itano, Seiji
AU - Yamamoto, Toshiya
AU - Satoh, Minoru
AU - Sasaki, Tamaki
AU - Suzuki, Takafumi
AU - Yamamoto, Masayuki
AU - Wigley, W. Christian
AU - Proksch, Joel W.
AU - Meyer, Colin J.
AU - Kashihara, Naoki
N1 - Funding Information:
The authors thank Etsuko Yorimasa, Yuriko Katayama, and Ayano Higashi (Kawasaki Medical School) for providing animal care, and Satomi Hanada, Keiko Shirakiya, and Keiko Satoh (Kawasaki Medical School) for assisting with the in vitro assays. The authors also thank Kyowa Hakko Kirin Co., Ltd. (Tokyo, Japan) for supporting the preparation of this manuscript. This work was supported, in part, by the Japan Society for the Promotion of Science (JSPS) Kakenhi Grants 24591220 and 18H02828 (to H.N. and N.K.), and Kawasaki Medical School Grant 30B-75 (to T.Y.). W. Christian Wigley, Joel W. Proksch, and Colin J. Meyer have ownership of Reata Pharmaceuticals stock. The remaining authors delcare no conflicts of interest.
Funding Information:
The authors thank Etsuko Yorimasa, Yuriko Katayama, and Ayano Higashi (Kawasaki Medical School) for providing animal care, and Satomi Hanada, Keiko Shirakiya, and Keiko Satoh (Kawasaki Medical School) for assisting with the in vitro assays. The authors also thank Kyowa Hakko Kirin Co., Ltd. (Tokyo, Japan) for supporting the preparation of this manuscript. This work was supported, in part, by the Japan Society for the Promotion of Science (JSPS) Kakenhi Grants 24591220 and 18H02828 (to H.N. and N.K.), and Kawasaki Medical School Grant 30B‐75 (to T.Y.). W. Christian Wigley, Joel W. Proksch, and Colin J. Meyer have ownership of Reata Pharmaceuticals stock. The remaining authors delcare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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. FASEB J. 33, 12253-12263 (2019). www.fasebj.org.
AB - 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. FASEB J. 33, 12253-12263 (2019). www.fasebj.org.
KW - Nrf2
KW - dh404
KW - inflammation
KW - reactive oxidative species
UR - http://www.scopus.com/inward/record.url?scp=85074378446&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074378446&partnerID=8YFLogxK
U2 - 10.1096/fj.201900217R
DO - 10.1096/fj.201900217R
M3 - Article
C2 - 31431054
AN - SCOPUS:85074378446
SN - 0892-6638
VL - 33
SP - 12253
EP - 12263
JO - FASEB Journal
JF - FASEB Journal
IS - 11
ER -
