Abstract
The mineralocorticoid receptor (MR) antagonists PF-03882845 and eplerenone were evaluated for renal protection against aldosterone-mediated renal disease in uninephrectomized Sprague-Dawley (SD) rats maintained on a high salt diet and receiving aldosterone by osmotic mini-pump for 27 days. Serum K+ and the urinary albumin to creatinine ratio (UACR) were assessed following 14 and 27 days of treatment. Aldosterone induced renal fibrosis as evidenced by increases in UACR, collagen IV staining in kidney cortex, and expression of pro-fibrotic genes relative to sham-operated controls not receiving aldosterone. While both PF-03882845 and eplerenone elevated serum K+ levels with similar potencies, PF-03882845 was more potent than eplerenone in suppressing the rise in UACR. PF-03882845 prevented the increase in collagen IV staining at 5, 15 and 50 mg/kg BID while eplerenone was effective only at the highest dose tested (450 mg/kg BID). All doses of PF-03882845 suppressed aldosterone-induced increases in collagen IV, transforming growth factor-β 1 (Tgf-β 1), interleukin-6 (Il-6), intermolecular adhesion molecule-1 (Icam-1) and osteopontin gene expression in kidney while eplerenone was only effective at the highest dose. The therapeutic index (TI), calculated as the ratio of the EC50 for increasing serum K+ to the EC50 for UACR lowering, was 83.8 for PF-03882845 and 1.47 for eplerenone. Thus, the TI of PF-03882845 against hyperkalemia was 57-fold superior to that of eplerenone indicating that PF-03882845 may present significantly less risk for hyperkalemia compared to eplerenone.
Highlights
Mounting clinical evidence suggests a key role for aldosterone in the progression of nephropathy
We investigated whether PF-03882845, a novel non-steroidal mineralocorticoid receptor (MR) antagonist, differentiates from traditional steroidal MR antagonists, such as eplerenone
Our results support the development of PF03882845 for the treatment of diabetic nephropathy, a condition in which the patient is at risk for hyperkalemia
Summary
Mounting clinical evidence suggests a key role for aldosterone in the progression of nephropathy. Inhibitors of the reninangiotensin-aldosterone system (RAAS), such as angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) have been demonstrated to delay the onset of macroalbuminuria or frank nephropathy in diabetics (Brenner et al, 2001; Lewis et al, 2001; Parving et al, 2001; Remuzzi et al, 2002; Ruggenenti et al, 2004). The mineralocorticoid receptor (MR) antagonist spironolactone effectively reduced UACR in diabetic nephropathy patients exhibiting “aldosterone escape” while on ACEI therapy (Sato et al, 2003). Eplerenone, another marketed MR antagonist, decreased UACR in type 2 diabetics with mild to moderate nephropathy to a greater extent than that achieved with ACEI treatment alone, and independently of changes in blood pressure (Epstein, 2006; Epstein et al, 2006). Under conditions of low blood volume or reduced renal perfusion, plasma angiotensin II (angII) and K+ levels increase and synergistically stimulate aldosterone secretion from the adrenals thereby promoting Na+ and water retention in the proximal tubule and driving sodium-dependent K+ secretion in the distal tubule of the kidney (Palmer, 2004)
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