TY - JOUR
T1 - The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells
AU - Ding, Yanfeng
AU - Stidham, Rhesa D.
AU - Bumeister, Ron
AU - Trevino, Isaac
AU - Winters, Ali
AU - Sprouse, Marc
AU - Ding, Min
AU - Ferguson, Deborah A.
AU - Meyer, Colin J.
AU - Christian Wigley, W.
AU - Ma, Rong
N1 - Funding Information:
The work was supported by National Institutes of Health of USA (5RO1DK079968-01A2, R Ma). This work was also supported in part by Reata Pharmaceuticals, Irving, TX. We thank Dr Scott Reisman and Dr Justin Rains for performing experiments to assess the enzymatic activity of Nrf2 target enzymes. We are also grateful to Drs Keith Ward and Jim McKay for their critical review and editing of the manuscript.
PY - 2013/5
Y1 - 2013/5
N2 - Bardoxolone methyl, a synthetic triterpenoid, improves the estimated glomerular filtration rate (GFR) in patients with chronic kidney disease and type 2 diabetes. Since the contractile activity of mesangial cells may influence glomerular filtration, we evaluated the effect of the synthetic triterpenoid RTA 405, with structural similarity to bardoxolone methyl, on GFR in rats and on mesangial cell contractility in freshly isolated glomeruli. In rats, RTA 405 increased basal GFR, assessed by inulin clearance, and attenuated the angiotensin II-induced decline in GFR. RTA 405 increased the filtration fraction, but did not affect arterial blood pressure or renal plasma flow. Glomeruli from RTA 405-treated rats were resistant to angiotensin II-induced volume reduction ex vivo. In cultured mesangial cells, angiotensin II-stimulated contraction was attenuated by RTA 405, in a dose-and time-dependent fashion. Further, Nrf2-targeted gene transcription (regulates antioxidant, anti-inflammatory, and cytoprotective responses) in mesangial cells was associated with decreased basal and reduced angiotensin II-stimulated hydrogen peroxide and calcium ion levels. These mechanisms contribute to the GFR increase that occurs following treatment with RTA 405 in rats and may underlie the effect of bardoxolone methyl on the estimated GFR in patients.
AB - Bardoxolone methyl, a synthetic triterpenoid, improves the estimated glomerular filtration rate (GFR) in patients with chronic kidney disease and type 2 diabetes. Since the contractile activity of mesangial cells may influence glomerular filtration, we evaluated the effect of the synthetic triterpenoid RTA 405, with structural similarity to bardoxolone methyl, on GFR in rats and on mesangial cell contractility in freshly isolated glomeruli. In rats, RTA 405 increased basal GFR, assessed by inulin clearance, and attenuated the angiotensin II-induced decline in GFR. RTA 405 increased the filtration fraction, but did not affect arterial blood pressure or renal plasma flow. Glomeruli from RTA 405-treated rats were resistant to angiotensin II-induced volume reduction ex vivo. In cultured mesangial cells, angiotensin II-stimulated contraction was attenuated by RTA 405, in a dose-and time-dependent fashion. Further, Nrf2-targeted gene transcription (regulates antioxidant, anti-inflammatory, and cytoprotective responses) in mesangial cells was associated with decreased basal and reduced angiotensin II-stimulated hydrogen peroxide and calcium ion levels. These mechanisms contribute to the GFR increase that occurs following treatment with RTA 405 in rats and may underlie the effect of bardoxolone methyl on the estimated GFR in patients.
KW - calcium
KW - glomerular filtration rate
KW - mesangial cells
KW - reactive oxygen species
KW - renal physiology
UR - http://www.scopus.com/inward/record.url?scp=84877058276&partnerID=8YFLogxK
U2 - 10.1038/ki.2012.393
DO - 10.1038/ki.2012.393
M3 - Article
C2 - 23235569
AN - SCOPUS:84877058276
SN - 0085-2538
VL - 83
SP - 845
EP - 854
JO - Kidney International
JF - Kidney International
IS - 5
ER -