title: The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells.
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.
authors.affiliation: Department of Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Ding
authors.forename: Rhesa D
authors.initials: RD
authors.lastname: Stidham
authors.forename: Ron
authors.initials: R
authors.lastname: Bumeister
authors.forename: Isaac
authors.initials: I
authors.lastname: Trevino
authors.forename: Ali
authors.initials: A
authors.lastname: Winters
authors.forename: Marc
authors.initials: M
authors.lastname: Sprouse
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Ferguson
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
authors.forename: W Christian
authors.initials: WC
authors.lastname: Wigley
authors.forename: Rong
authors.initials: R
authors.lastname: Ma
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007444:Inulin / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013997:Time Factors
chemical_list: C518860:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495637:Nfe2l2 protein, rat; D000804:Angiotensin II; D009828:Oleanolic Acid; D007444:Inulin; D006861:Hydrogen Peroxide; D002118:Calcium