Identification of target molecule for the treatment of progressive renal diseases and its application for gene therapy.

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Single injection of anti Thy1.1 monoclonal antibody, 1-22-3, induces reversible glomerulonephritis in the rats, whereas the same single injection after heminephrectomy induces irreversible progressive glomerulonephritis. To identify the novel genes, which play important roles in the progression of renal diseases, we made these two rat models, reversible and irreversible glomemlonephritis rats, and extracted RNA from the kidneys for microarray analysis, periodically. The differences of gene expression between two models were analyzed and the differences of more than 2 time increase or 50% reduction were considered as significant By this definition, 191 genes showed significant changes and cluster analysis was performed. These 191 genes were classified into 7 clusters and one cluster contained laminin, collagen type I, KIM-1, and osteopontin, which showed increase during the course of the progression of renal impairment in the irreversible model rats. Thymosin β-10 is also included in th … More is cluster and immunohistological study revealed that thymosin β-10 is present in the interstitial tissues with progression of the renal impairment In the cultured THP-1 cells, human macrophage cell line, it was shown that expression of thymosin β-10 increased with the differentiation of THP-1 cells to macrophage. These results suggest that thymosin β-10 may play important roles in the activation of infiltrated macrophage and induction of interstitial damages. We are currently working on the possibility of the target gene of the therapy for progressive renal diseases.Injection of massive bovine serum albumin into abdominal cavity is known to induce proteinuria and thereby induces renal interstitial impairment In this model, NF-κB is thought to play a pivotal role. To specify the molecules of renal interstitial impairment, we analyzed gene expression differences between control proteinuric rats induced by injection of massive bovine serum albumin and proteinuric rats received adenoviral gene transfer of truncated form IκBα, which inhibits NF-κB activation in the proximal tubules. Microarray analysis identified progressive factors and protective factors of pioteinuria-induced interstitial impairment through the activation of NF-κB. In this analysis, clusterin was identified as protective factor. In addition, angiotensin converting enzyme type 2 showed decrease with proteinuria and increase with inhibition of NF-κB, suggesting that decrease of this enzyme might result in the activation of renin-angiotensin system in the kidney. Angiotensin converting enzyme type 2 may become a target gene of the treatment of progressive renal diseases. Less