title: Suppression of Rapidly Progressive Mouse Glomerulonephritis with the Non-Steroidal Mineralocorticoid Receptor Antagonist BR-4628.
abstract: OBJECTIVE
  Steroidal mineralocorticoid receptor antagonists (MRAs) are effective in the treatment of kidney disease; however, the side effect of hyperkalaemia, particularly in the context of renal impairment, is a major limitation to their clinical use. Recently developed non-steroidal MRAs have distinct characteristics suggesting that they may be superior to steroidal MRAs. Therefore, we explored the benefits of a non-steroidal MRA in a model of rapidly progressive glomerulonephritis.
  
  
  METHODS
  Accelerated anti-glomerular basement membrane (GBM) glomerulonephritis was induced in groups of C57BL/6J mice which received no treatment, vehicle or a non-steroidal MRA (BR-4628, 5mg/kg/bid) from day 0 until being killed on day 15 of disease. Mice were examined for renal injury.
  
  
  RESULTS
  Mice with anti-GBM glomerulonephritis which received no treatment or vehicle developed similar disease with severe albuminuria, impaired renal function, glomerular tuft damage and crescents in 40% of glomeruli. In comparison, mice which received BR-4628 displayed similar albuminuria, but had improved renal function, reduced severity of glomerular tuft lesions and a 50% reduction in crescents. The protection seen in BR-4628 treated mice was associated with a marked reduction in glomerular macrophages and T-cells and reduced kidney gene expression of proinflammatory (CCL2, TNF-α, IFN-γ) and profibrotic molecules (collagen I, fibronectin). In addition, treatment with BR-4626 did not cause hyperkalaemia or increase urine Na+/K+ excretion (a marker of tubular dysfunction).
  
  
  CONCLUSIONS
  The non-steroidal MRA (BR-4628) provided substantial suppression of mouse crescentic glomerulonephritis without causing tubular dysfunction. This finding warrants further investigation of non-steroidal MRAs as a therapy for inflammatory kidney diseases.
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.|Department of Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.|Department of Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.|Department of Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.affiliation: Department of Cardiology Research, Global Drug Discovery, Bayer HealthCare, Wuppertal, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.|Department of Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: Greg H
authors.initials: GH
authors.lastname: Tesch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D005260:Female; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000608139:BR-4628; D002867:Chromones; D004095:Dihydropyridines; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger