Suppression of Rapidly Progressive Mouse Glomerulonephritis with the Non-Steroidal Mineralocorticoid Receptor Antagonist BR-4628.

Abstract

BACKGROUND/AIM:

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: Frank Y Ma, Yingjie Han, David J Nikolic-Paterson, Peter Kolkhof, Greg H Tesch
• Journal: PloS one (PLoS One) Vol. 10 Issue 12 Pg. e0145666 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26700873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BR-4628
• Chromones
• Dihydropyridines
• Mineralocorticoid Receptor Antagonists
• RNA, Messenger

Topics

• Animals
• Cells, Cultured
• Chromones (pharmacology)
• Dihydropyridines (pharmacology)
• Female
• Glomerulonephritis (metabolism, pathology, prevention & control)
• Immunoenzyme Techniques
• Kidney Function Tests
• Kidney Glomerulus (drug effects, metabolism, pathology)
• Macrophages (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mineralocorticoid Receptor Antagonists (pharmacology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction