Abstract
Background/AimSteroidal 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.MethodsAccelerated 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.ResultsMice 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).ConclusionsThe 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.
Highlights
Steroidal mineralocorticoid receptor antagonists (MRAs) can inhibit kidney injury in animal models of glomerulonephritis and diabetic nephropathy independent of blood pressure effects. [3,4,5,6,7,8] In addition, steroidal MRAs have consistently provided added protection in glomerulonephritis and diabetic nephropathy in clinical trials when used in conjunction with reninangiotensin system (RAS) blockade, which supports their use as an adjunct therapy.[9,10,11]
A further downside of steroidal MRA therapy is that it can cause hyperkalaemia in patients, which is a major clinical concern, in the context of renal impairment, and necessitates withdrawal of this treatment.[9]. This problem arises because steroidal MRAs inhibit aldosterone-based activation of ion channels in tubular epithelial cells which is essential for sodium and potassium homeostasis
There was a 1000-fold increase in the urine albumin excretion at day 1 of glomerulonephritis, which increased 3-fold further at day 7 of disease and remained stable between days 7 and 14 of disease (Fig 1A)
Summary
Steroid-based mineralocorticoid receptor (MR) antagonists (spironolactone and eplerenone) provide protection against kidney and cardiovascular disease through both local tissue effects and by reducing hypertension.[1,2] Steroidal MRAs can inhibit kidney injury in animal models of glomerulonephritis and diabetic nephropathy independent of blood pressure effects. [3,4,5,6,7,8] In addition, steroidal MRAs have consistently provided added protection in glomerulonephritis and diabetic nephropathy in clinical trials when used in conjunction with reninangiotensin system (RAS) blockade (the current standard therapy), which supports their use as an adjunct therapy.[9,10,11]Despite their therapeutic benefits, steroidal MRAs have drawbacks which limit their clinical use. In addition to binding to the MR, spironolactone binds to progesterone and androgen receptors leading to adverse progestational and anti-androgenic effects (including gynecomastia, breast tenderness, impotence and menstrual irregularities).[12] In comparison, eplerenone is more selective, but has weaker affinity for binding MR and is less potent than spironolactone.[12] Eplerenone is metabolised by the ubiquitous cytochrome (CYP) 3A4 and drugs or antibiotics that inhibit CYP3A4 can precipitate eplerenone toxicity.[12] A further downside of steroidal MRA therapy is that it can cause hyperkalaemia in patients, which is a major clinical concern, in the context of renal impairment, and necessitates withdrawal of this treatment.[9] This problem arises because steroidal MRAs inhibit aldosterone-based activation of ion channels in tubular epithelial cells which is essential for sodium and potassium homeostasis. It is desirable to develop a therapy which can inhibit pathological MR signaling while having a minimal effect on potassium homeostasis
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