BACKGROUND: An oral adsorbent, AST-120, is effective in removing such uremic toxins as indoxyl sulfate and delays the progression of chronic renal failure. To elucidate the molecular mechanisms underlying the renoprotective effects of AST-120, the complementary DNA (cDNA) array method was used to survey the alteration in gene expression profiles of uremic rat kidneys in response to AST-120. METHODS: Six weeks after five-sixth nephrectomy, 10 uremic rats were divided into two groups: those administered AST-120 and control uremic rats. Rats subjected to sham operation also were included as normal rats. After administration of AST-120 for 18 weeks, renal tissues were analyzed by cDNA array. RESULTS: Among the 343 genes selected as expressed, control uremic rats showed significantly increased levels of 139 genes and significantly decreased levels of 45 genes compared with normal rats. AST-120 treatment attenuated expression levels of 43 of the 139 upregulated renal genes and 21 of the 45 downregulated renal genes in uremic rat kidney. Those genes could be subdivided into several functional categories, including cytokine (transforming growth factor-beta1 [TGF-beta1], etc), intracellular signaling, transcription, translation, channel and transporter (organic anion transporter 1 [OAT1], etc), metabolism, and protease and its inhibitor. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that AST-120 significantly increased OAT1 renal expression and tended to decrease TGF-beta1, tissue inhibitor of metalloproteinase-1 (TIMP-1), and endothelin-1 renal expression in uremic rats. There were statistically significant positive correlations between cDNA array-based and RT-PCR-based gene expression levels of TGF-beta1, TIMP-1, and endothelin-1. CONCLUSION: The cDNA array method determines changes in the gene expression profile in uremic rat kidney in response to AST-120 and provides new insights into elucidation of the molecular mechanism underlying the renoprotective effects of AST-120.
BACKGROUND: An oral adsorbent, AST-120, is effective in removing such uremic toxins as indoxyl sulfate and delays the progression of chronic renal failure. To elucidate the molecular mechanisms underlying the renoprotective effects of AST-120, the complementary DNA (cDNA) array method was used to survey the alteration in gene expression profiles of uremic rat kidneys in response to AST-120. METHODS: Six weeks after five-sixth nephrectomy, 10 uremic rats were divided into two groups: those administered AST-120 and control uremic rats. Rats subjected to sham operation also were included as normal rats. After administration of AST-120 for 18 weeks, renal tissues were analyzed by cDNA array. RESULTS: Among the 343 genes selected as expressed, control uremic rats showed significantly increased levels of 139 genes and significantly decreased levels of 45 genes compared with normal rats. AST-120 treatment attenuated expression levels of 43 of the 139 upregulated renal genes and 21 of the 45 downregulated renal genes in uremic rat kidney. Those genes could be subdivided into several functional categories, including cytokine (transforming growth factor-beta1 [TGF-beta1], etc), intracellular signaling, transcription, translation, channel and transporter (organic anion transporter 1 [OAT1], etc), metabolism, and protease and its inhibitor. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that AST-120 significantly increased OAT1 renal expression and tended to decrease TGF-beta1, tissue inhibitor of metalloproteinase-1 (TIMP-1), and endothelin-1 renal expression in uremic rats. There were statistically significant positive correlations between cDNA array-based and RT-PCR-based gene expression levels of TGF-beta1, TIMP-1, and endothelin-1. CONCLUSION: The cDNA array method determines changes in the gene expression profile in uremic rat kidney in response to AST-120 and provides new insights into elucidation of the molecular mechanism underlying the renoprotective effects of AST-120.
Authors: Xiao-Yan Chu; Yuexia Liang; Xiaoxin Cai; Karla Cuevas-Licea; Ronda K Rippley; Kelem Kassahun; Magang Shou; Matthew P Braun; George A Doss; M Reza Anari; Raymond Evers Journal: Pharm Res Date: 2008-12-11 Impact factor: 4.200