An oral adsorbent downregulates renal expression of genes that promote interstitial inflammation and fibrosis in diabetic rats.
OBJECTIVE
An oral adsorbent, AST-120, removes uremic toxins such as indoxyl sulfate, and delays the progression of renal failure. This study was designed to investigate the effects of AST-120 on the molecular basis of interstitial inflammation and fibrosis, using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus.


METHODS
Four weeks after unilateral nephrectomy, the uninephrectomized OLETF (1/2NxOLETF) rats were divided into two groups: AST-120-administered and control 1/2NxOLETF rats. After the administration of AST-120 for 48 weeks, we examined the effects of AST-120 on renal functional, pathological, and gene expressional changes.


RESULTS
The administration of AST-120 to the 1/2NxOLETF rats attenuated the progression of renal dysfunction, proteinuria, glomerular sclerosis, tubular injury, and interstitial inflammation and fibrosis. AST-120 significantly reduced renal expression of intercellular adhesion molecule (ICAM)-1, osteopontin, monocyte chemotactic protein (MCP)-1, and transforming growth factor (TGF)-beta1, as well as clusterin. All the five molecules were expressed mainly in tubular cells. AST-120 also decreased serum and urinary levels of indoxyl sulfate and the overload of indoxyl sulfate in tubular cells.


CONCLUSIONS
AST-120 ameliorates tubulointerstitial injury by reducing renal expression of ICAM-1, osteopontin, MCP-1, TGF-beta1 and clusterin in 1/2NxOLETF rats.
Aoyama
Isao
I
Nagoya University Hospital, Nagoya, Japan.
Shimokata
Kaoru
K
Niwa
Toshimitsu
T
D000284:Administration, Oral; D000327:Adsorption; D000818:Animals; D015152:Blotting, Northern; D002244:Carbon / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics; D051152:Clusterin; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects* / Q000276:immunology; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics; D007150:Immunohistochemistry; D007200:Indican / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D008297:Male; D018832:Molecular Chaperones / Q000032:analysis / Q000235:genetics; D053495:Osteopontin; D010087:Oxides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics; D053773:Transforming Growth Factor beta1
D018932:Chemokine CCL2; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D010087:Oxides; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D018799:Intercellular Adhesion Molecule-1; D002244:Carbon; C040896:AST 120; D007200:Indican