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The influence of enalapril or spironolactone on experimental cyclosporin nephrotoxicity
Abstract:
Adult Sprague-Dawley rats treated daily for 14 days with 50 mg/kg cyclosporin A (CsA) exhibited nephrotoxicity, characterized by reduced glomerular filtration rate, decreased urinary sodium and potassium flow, tubular enzymuria and proximal tubular structural damage. Elevations in plasma renin activity (PRA) were observed on day 4, but returned to normal within 7 days. Co-treatment of animals for the 14 day period with enalapril (8 mg/kg/day), a potent inhibitor of angiotensin converting enzyme (ACE), or spironolactone (25 mg/kg/day), the distal tubular antagonist of aldosterone, reduced the nephrotoxicity, although PRA remained elevated. Neither enalapril nor spironolactone affected circulating CsA levels. These data suggest that the action of aldosterone on the distal tubule may be important in the pathogenesis of CsA nephrotoxicity.
Insights
Cyclosporin A (CsA) causes kidney damage in rats. Blocking aldosterone with spironolactone or angiotensin-converting enzyme (ACE) with enalapril reduced this CsA-induced nephrotoxicity, suggesting aldosterone
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Cyclosporin A (CsA) is an immunosuppressant drug known to cause nephrotoxicity.
- The exact mechanisms underlying CsA-induced kidney damage are not fully understood.
- Aldosterone and the renin-angiotensin-aldosterone system (RAAS) are implicated in kidney function and disease.
Purpose of the Study:
- To investigate the role of aldosterone in the pathogenesis of CsA-induced nephrotoxicity.
- To evaluate the renoprotective effects of ACE inhibitors and aldosterone antagonists against CsA toxicity.
Main Methods:
- Adult Sprague-Dawley rats were treated with CsA (50 mg/kg/day) for 14 days.
- Rats received co-treatment with enalapril (an ACE inhibitor) or spironolactone (an aldosterone antagonist).
- Kidney function was assessed by measuring glomerular filtration rate, urinary electrolyte and enzyme excretion, and histological damage. Plasma renin activity (PRA) was also monitored.
Main Results:
- CsA treatment led to significant nephrotoxicity, including reduced GFR and tubular damage.
- Elevated PRA was observed early in CsA treatment but normalized within 7 days.
- Co-administration of enalapril or spironolactone attenuated CsA-induced nephrotoxicity, despite sustained elevated PRA.
- Neither enalapril nor spironolactone altered circulating CsA levels.
Conclusions:
- The findings suggest that aldosterone's action on the distal tubule plays a significant role in the development of CsA nephrotoxicity.
- Inhibition of the renin-angiotensin-aldosterone system, particularly aldosterone's effects, may offer a therapeutic strategy to mitigate CsA-induced kidney damage.