Angiotensin II accelerates and renin angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin II. It was the aim of this study to assess the relative ability of an angiotensin receptor type 1 (AT₁) blocker, a mineralocorticoid receptor blocker and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery they were either sacrificed or allocated to treatment with vehicle, Losartan, Spironolactone, their combination, or unspecific antihypertensive treatment (Dihydralazine) for 4 weeks. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared to sham-op animals and decreased in all treatment groups. Compared to week 8 after SNX the glomerulosclerosis index (GSI) had increased further by the 12th week in the vehicle and Dihydralazine treated groups, but was significantly lowered in the SNX+Losartan as well as in the SNX+Losartan+Spironolactone groups and had not progressed further in the SNX+Spironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats after high dose AT1-R blockade. Non-hyperkalemic doses of Spironolactone prevented the increase of, but failed to decrease the glomerulosclerosis index below the 8 week level and preserved podocyte numbers. Combining the AT₁ blocker with mineralocorticoid receptor blockade failed to further increase regression of glomerulosclerosis.