The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells

Yanfeng Ding, Rhesa D. Stidham, Ron Bumeister, Isaac Trevino, Ali Winters, Marc Sprouse, Min Ding, Deborah A. Ferguson, Colin J. Meyer, W. Christian Wigley, Rong Ma

Research output: Contribution to journalArticleResearchpeer-review

31 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)845-854
Number of pages10
JournalKidney International
Volume83
Issue number5
DOIs
StatePublished - 1 Jan 2013

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Mesangial Cells
Glomerular Filtration Rate
Angiotensin II
Renal Plasma Flow
Inulin
Chronic Renal Insufficiency
Type 2 Diabetes Mellitus
Hydrogen Peroxide
2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide
Cultured Cells
Arterial Pressure
Anti-Inflammatory Agents
Antioxidants
Ions
Calcium
Genes
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate

Keywords

  • calcium
  • glomerular filtration rate
  • mesangial cells
  • reactive oxygen species
  • renal physiology

Cite this

Ding, Yanfeng ; Stidham, Rhesa D. ; Bumeister, Ron ; Trevino, Isaac ; Winters, Ali ; Sprouse, Marc ; Ding, Min ; Ferguson, Deborah A. ; Meyer, Colin J. ; Christian Wigley, W. ; Ma, Rong. / The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells. In: Kidney International. 2013 ; Vol. 83, No. 5. pp. 845-854.
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abstract = "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.",
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Ding, Y, Stidham, RD, Bumeister, R, Trevino, I, Winters, A, Sprouse, M, Ding, M, Ferguson, DA, Meyer, CJ, Christian Wigley, W & Ma, R 2013, 'The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells', Kidney International, vol. 83, no. 5, pp. 845-854. https://doi.org/10.1038/ki.2012.393

The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells. / Ding, Yanfeng; Stidham, Rhesa D.; Bumeister, Ron; Trevino, Isaac; Winters, Ali; Sprouse, Marc; Ding, Min; Ferguson, Deborah A.; Meyer, Colin J.; Christian Wigley, W.; Ma, Rong.

In: Kidney International, Vol. 83, No. 5, 01.01.2013, p. 845-854.

Research output: Contribution to journalArticleResearchpeer-review

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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

PY - 2013/1/1

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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

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