Effect of combining ACE inhibition with aldosterone blockade on proteinuria and renal damage in experimental nephrosis.
Aldosterone has pro-fibrotic properties and is a potential target for additional intervention in patients with chronic renal disease showing resistance to therapy during treatment with angiotensin-converting enzyme inhibitors (ACEi). Combining ACEi and aldosterone receptor blockade (aldoRB) in proteinuric renal disease reduces proteinuria, but effects on proteinuria-induced renal damage are unknown. We studied the effect of ACEi/aldoRB in adriamycin nephrosis (AN). Six weeks after injection of adriamycin in Wistar rats, randomized treatment with vehicle (VEH, n=8), aldoRB (n=12), ACEi (n=10), or a combination of ACEi/aldoRB (n=14) was given for 12 weeks. Healthy rats served as controls (n=6). Renal damage was quantified by markers of tubular injury (osteopontin (OPN) and kidney injury molecule-1 (Kim-1)), pre-fibrotic lesions (alpha-smooth muscle actin (SMA)), interstitial fibrosis (IF), and focal glomerulosclerosis (FGS). In AN animals, proteinuria was increased compared with controls. ACEi and ACEi/aldoRB significantly reduced proteinuria compared with VEH, whereas aldoRB monotherapy was without effect. Blood pressure was reduced in ACEi and ACEi/aldoRB compared with VEH and aldoRB. OPN and Kim-1 were increased in AN animals, but significantly reduced by ACEi/aldoRB. Treatment with ACEi and ACEi/aldoRB prevented an increase of SMA, IF, and FGS. In conclusion, ACEi/aldoRB effectively reduced proteinuria and markers of tubular injury and prevented renal damage in this rat model of chronic proteinuria-induced renal damage.
Kramer
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Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
van der Meulen
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EF
Hamming
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van Goor
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H
Navis
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D000199:Actins / Q000032:analysis; D000450:Aldosterone / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000032:analysis; D024141:Collagen Type IV / Q000032:analysis; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005923:Glomerulosclerosis, Focal Segmental / Q000517:prevention & control; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D008565:Membrane Proteins / Q000032:analysis; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D009401:Nephrosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D053495:Osteopontin / Q000032:analysis; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011507:Proteinuria / Q000150:complications / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar
D000199:Actins; D000450:Aldosterone; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D024141:Collagen Type IV; D008565:Membrane Proteins; D000451:Mineralocorticoid Receptor Antagonists; D053495:Osteopontin; D007703:Peptidyl-Dipeptidase A; C110936:Havcr1 protein, rat; C498862:Acta2 protein, rat