title: Blood pressure-independent additive effects of pharmacologic blockade of the renin-angiotensin and endothelin systems on progression in a low-renin model of renal damage.
abstract: Pharmacologic blockade of the renin and endothelin (ET) systems is an established strategy to interfere with progression of renal failure. In the Heyman nephritis model, additive benefits of decreases in BP with the combination of angiotensin-converting enzyme inhibitors (ACE-i) and ET(A) receptor antagonists (ET-RA) were demonstrated. To further investigate these findings and to exclude confounding effects of BP decreases, this issue was reassessed in a low-renin model of subtotal kidney resection. Subtotally nephrectomized (SNX) and sham-operated rats were left untreated or received an ACE-i, an angiotensin II subtype 1 receptor antagonist (AT1-RA), an ET-RA, or combinations thereof (ACE-i plus ET-RA or AT1-RA plus ET-RA). The parameters studied were the glomerulosclerosis index (GSI), tubulointerstitial index, vascular damage index, glomerular geometry, and albumin excretion. After 12 wk, BP values were comparable. Urinary albumin excretion rates were significantly higher for untreated SNX rats (24.3 +/- 31.3 mg/24 h), compared with untreated sham-operated rats (0.71 +/- 0.40 mg/24 h). Rates were significantly lower for all treated, compared with untreated, SNX groups. GSI values were significantly higher for untreated SNX rats than for untreated sham-operated rats. ACE-i caused significantly lower GSI in SNX rats (0.46 +/- 0.06), compared with AT1-RA (0.60 +/- 0.10) or ET-RA (0.65 +/- 0.10). GSI values were significantly decreased further with ACE-i plus ET-RA (0.29 +/- 0.09) or AT1-RA plus ET-RA (23 +/- 0.05) treatment. Changes in the tubulointerstitial index and vascular damage index proceeded in parallel. The results document BP-independent effects of the ACE-i and AT1-RA on the GSI and urinary albumin excretion and an effect of the ET-RA on the GSI. The contrasting results suggest different pathogenetic pathways for glomerulosclerosis and albuminuria. The combination of treatments provided superior effects on the GSI and tubulointerstitial index but not on urinary albumin excretion.
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Simonaviciene
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Medwedewa
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koch
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Orth
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Gross
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haas
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kuhlmann
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Linz
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Bernward
authors.initials: B
authors.lastname: Schölkens
authors.affiliation: Departments of *Pathology and Internal Medicine, University of Erlangen, Erlangen, Germany; Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany; Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland; and Aventis Pharma, Frankfurt, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Ritz
mesh_terms: D000419:Albuminuria / Q000652:urine; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D018450:Disease Progression; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009318:Natriuresis; D009392:Nephrectomy / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D012083:Renin