title: Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination.
abstract: 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. The purpose of this study was 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 euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 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 receptor blockade. Nonhyperkalemic doses of spironolactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the AT1 blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis.
authors.affiliation: Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany. g.piecha@gmx.de
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Piecha
authors.forename: Nadezda
authors.initials: N
authors.lastname: Koleganova
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Gross
authors.forename: Aman
authors.initials: A
authors.lastname: Geldyyev
authors.forename: Marcin
authors.initials: M
authors.lastname: Adamczak
authors.forename: Eberhard
authors.initials: E
authors.lastname: Ritz
mesh_terms: D000419:Albuminuria / Q000652:urine; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D024141:Collagen Type IV / Q000096:biosynthesis; D003893:Desmin / Q000096:biosynthesis; D004078:Dihydralazine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D016328:NF-kappa B / Q000096:biosynthesis; D009392:Nephrectomy; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013148:Spironolactone / Q000008:administration & dosage / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D024141:Collagen Type IV; D003893:Desmin; D000451:Mineralocorticoid Receptor Antagonists; D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C095477:platelet-derived growth factor AB; C467498:vascular endothelial growth factor A, rat; D013148:Spironolactone; D040301:Vascular Endothelial Growth Factor Receptor-2; D019808:Losartan; D004078:Dihydralazine