BACKGROUND: A close correlation has been shown between tubulointerstitial (TI) injury and the outcome of renal dysfunction, and nuclear factor-kappaB (NFkappaB) has been shown to play a key role in proteinuria-induced TI injury. To explore the molecular mechanisms of the proteinuria-induced TI injury further, we have analyzed renal gene expression with DNA microarrays, with and without specific inhibition of NF-kappaB in the proximal tubules. METHODS: Unilaterally nephrectomized rats loaded with bovine serum albumin (BSA) were used as a model of proteinuric renal injury. Renal NF-kappaB activation was inhibited by gene transfer of the truncated form of IkappaBalpha (inhibitor of NF-kappaB) via the injection of a recombinant adenovirus vector into the renal artery, an method established in a previous study. Total RNA was extracted from the kidney and analyzed with a DNA microarrays containing 1081 genes. RESULTS: Renal NF-kappaB activation and TI injury in BSA-loaded proteinuric rats were inhibited by the gene transfer of the truncated form of IkappaBalpha. DNA microarray analysis revealed 45 up-regulated genes and six down-regulated genes in the proteinuric rats, and expression of 23 of these 51 genes was significantly altered by NF-kappaB inhibition. Among these 23 genes, we focused on clusterin and confirmed the results of microarray analysis by Western blotting and PCR. CONCLUSION: In this study, 23 genes of 51 proteinuria-related genes were regulated by NF-kappaB activation, suggesting that some of these genes may serve as target molecules for the treatment of progressive TI injury.
BACKGROUND: A close correlation has been shown between tubulointerstitial (TI) injury and the outcome of renal dysfunction, and nuclear factor-kappaB (NFkappaB) has been shown to play a key role in proteinuria-induced TI injury. To explore the molecular mechanisms of the proteinuria-induced TI injury further, we have analyzed renal gene expression with DNA microarrays, with and without specific inhibition of NF-kappaB in the proximal tubules. METHODS: Unilaterally nephrectomized rats loaded with bovine serum albumin (BSA) were used as a model of proteinuric renal injury. Renal NF-kappaB activation was inhibited by gene transfer of the truncated form of IkappaBalpha (inhibitor of NF-kappaB) via the injection of a recombinant adenovirus vector into the renal artery, an method established in a previous study. Total RNA was extracted from the kidney and analyzed with a DNA microarrays containing 1081 genes. RESULTS: Renal NF-kappaB activation and TI injury in BSA-loaded proteinuric rats were inhibited by the gene transfer of the truncated form of IkappaBalpha. DNA microarray analysis revealed 45 up-regulated genes and six down-regulated genes in the proteinuric rats, and expression of 23 of these 51 genes was significantly altered by NF-kappaB inhibition. Among these 23 genes, we focused on clusterin and confirmed the results of microarray analysis by Western blotting and PCR. CONCLUSION: In this study, 23 genes of 51 proteinuria-related genes were regulated by NF-kappaB activation, suggesting that some of these genes may serve as target molecules for the treatment of progressive TI injury.
Authors: Honglai Zhang; Jin Koo Kim; Chris A Edwards; Zhaohui Xu; Russell Taichman; Cun-Yu Wang Journal: Nat Cell Biol Date: 2005-08-21 Impact factor: 28.824
Authors: M Sumitomo; M Tachibana; C Ozu; H Asakura; M Murai; M Hayakawa; H Nakamura; A Takayanagi; N Shimizu Journal: Hum Gene Ther Date: 1999-01-01 Impact factor: 5.695