title: Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects.
abstract: Bardoxolone methyl is an antioxidant inflammation modulator acting through induction of Keap1-Nrf2 pathway. Results from a recent phase IIb clinical trial reported that bardoxolone methyl was associated with improvement in the estimated glomerular filtration rate in patients with advanced chronic kidney disease and Type 2 diabetes. However, increases in albuminuria, serum transaminase, and frequency of adverse events were noted. We studied the effect of 3-mo treatment with RTA 405, a synthetic triterpenoid analog of bardoxolone methyl in Zucker diabetic fatty rats with overt Type 2 diabetes. Rats were treated from 3 mo of age with vehicle, RTA 405, ramipril, or RTA 405 plus ramipril. RTA 405 caused severe changes in food intake and diuresis with decline in body weight, worsening of dyslipidemia, and increase in blood pressure. Early elevation in serum transaminase was followed by liver injury. RTA 405 worsened proteinuria, glomerulosclerosis, and tubular damage. Ramipril was renoprotective, but when given with RTA 405 it was not able to limit its worsening effects. These data could be due to degradation products in the drug substance used, as disclosed by the company once the study was concluded. To overcome such a drawback, the company offered to test dh404, a variant of RTA 405, in Zucker diabetic fatty rats. The dh404 did not display beneficial effects on proteinuria, glomerulosclerosis, and interstitial inflammation. Rather, kidneys from three rats receiving dh404 showed the presence of a granulomatous and inflammatory process reminiscent of a pseudotumor. Altogether these data raise serious concerns on the use of bardoxolone analogs in Type 2 diabetic nephropathy.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Zoja
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.forename: Valeria
authors.initials: V
authors.lastname: Nava
authors.forename: Monica
authors.initials: M
authors.lastname: Locatelli
authors.forename: Mauro
authors.initials: M
authors.lastname: Abbate
authors.forename: Flavio
authors.initials: F
authors.lastname: Gaspari
authors.forename: Fabiola
authors.initials: F
authors.lastname: Carrara
authors.forename: Fabio
authors.initials: F
authors.lastname: Sangalli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002853:Chromatography, Liquid; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D009828:Oleanolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives*; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D012079:Renal Circulation / Q000187:drug effects; D014315:Triterpenes / Q000009:adverse effects*
chemical_list: C518860:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide; D000806:Angiotensin-Converting Enzyme Inhibitors; D014315:Triterpenes; C547749:dh404 compound; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D017257:Ramipril