Angiotensin II receptor blockade blocker pre-treatment largely prevents injury from gradual renal ablation in rats

Abstract

INTRODUCTION: Reduction in renal mass in rats results in progressive proteinuria, hypertension, focal-segmental glomerulosclerosis (FSG), atrophy of tubules (AT), and interstitial expansion. We reported that slow reduction of renal tissue in rats (slow ablation) ending in the removal of 1.5 kidneys is associated, over the next six months, with higher albumin excretion rates (AER) and accelerated development of FSG lesions compared to sudden equivalent renal mass reduction. It was hypothesised that slow reduction of nephron numbers allows for a process of conditioning of residual nephrons that increases their susceptibility to subsequent injury. METHODS: To test this idea we treated Münich-Wistar rats with the angiotensin receptor blocker (ARB) losartan for six weeks during the gradual staged surgical removal of 1.5 kidneys, and compared them to sham operated controls, and parallel groups untreated by losartan. RESULTS: Despite discontinuation of losartan over the subsequent six months, ARB pre-treatment completely prevented proteinuria and hypertension in these slow renal ablation rats. ARB pre-treatment also largely prevented the subsequent development of FSG, AT, and interstitial expansion in these animals. Both losartan-treated and untreated renal ablation groups had glomerular enlargement and compensatory hyperfiltration and this was uninfluenced by losartan. CONCLUSION: Temporary ARB administration during gradual renal mass reduction resulted in long-term prevention of hypertension and albuminuria and greatly reduced FSG and tubular and interstitial lesions. We hypothesise that the preconditioning of residual nephrons in the gradual ablation model which facilitates their subsequent injury, is blunted by renin-angiotensin system blockade.