Combination therapy with benazepril and oral adsorbent ameliorates progressive renal fibrosis in uremic rats.
OBJECTIVE
The administration of an angiotensin-converting enzyme (ACE) inhibitor or an oral adsorbent, AST-120 (Kremezin), prevents the progression of renal failure. This study was designed to determine the additional effects of AST-120 combined with an ACE inhibitor, benazepril, on the progression of renal fibrosis in uremic rats.


METHODS
5/6-nephrectomized uremic rats were divided into control uremic rats (CRF group), benazepril-treated uremic rats (CRF+B group) and uremic rats receiving benazepril and AST-120 (CRF+BK group). After 14 weeks of treatment renal function and pathological changes were investigated.


RESULTS
The progression of renal dysfunction was delayed in both the CRF+B and CRF+BK groups as compared with the CRF group. In the CRF+BK group, the level of serum and urinary indoxyl sulfate and the tubular accumulation of indoxyl sulfate decreased. Both the CRF+B and CRF+BK groups showed lower glomerular sclerosis indices than the CRF group. In the CRF+BK group, but not the CRF+B group, the interstitial fibrosis area and the expression of transforming growth factor (TGF) beta1 and tissue inhibitor of metalloproteinases (TIMP) 1 were decreased as compared with the CRF group. Furthermore, the CRF+BK group showed a smaller interstitial fibrosis area and a lower renal osteopontin expression than the CRF+B group.


CONCLUSIONS
Combination therapy of benazepril and AST-120 is more effective than benazepril alone in retarding the progression of interstitial fibrosis by reducing the expression of TGF-beta 1, TIMP-1 and osteopontin.
Aoyama
Isao
I
Nagoya University Hospital, Nagoya, Japan.
Shimokata
Kaoru
K
Niwa
Toshimitsu
T
D000327:Adsorption; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001552:Benzazepines / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D002244:Carbon / Q000627:therapeutic use*; D002478:Cells, Cultured; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D017403:In Situ Hybridization; D007200:Indican / Q000097:blood / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D009400:Nephrosclerosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D053495:Osteopontin; D010087:Oxides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014511:Uremia / Q000188:drug therapy*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D010087:Oxides; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D002244:Carbon; C040896:AST 120; D007200:Indican; C044946:benazepril