Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo.

Maeshima, Yohei; Kashihara, Naoki; Yasuda, Tatsuji; Sugiyama, Hiroshi; Sekikawa, Takashi; Okamoto, Kazunori; Kanao, Koichiro; Watanabe, Yoshihiko; Kanwar, Yashpal S.; Makino, Hírofumi

doi:10.1172/jci429

Cited by 82 publications

(44 citation statements)

References 61 publications

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“…[13][14][15][16] To date, molecular therapeutic strategies using decoy ODN in glomerulonephritis have successfully focused on the direct effect of decoy ODN for transcription factor E2F or nuclear factor (NF)-kB. [17][18][19][20] These transcription factors are related with cell cycle progression and inflammatory diseases after glomerular injury. Another transcription factor AP-1 binds to AP-1 consensus sequences present in numerous genes associated with cell-proliferative response and ECM production, such as TGF-b1, collagen, and PAI-1.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo

Ahn

Morishita²,

Kaneda³

et al. 2004

Gene Ther

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Diabetic nephropathy is characterized by an expansion of glomerular mesangium, caused by mesangial cell proliferation and excessive accumulation of extracellular matrix (ECM) proteins, which eventually leads to glomerulosclerosis and renal failure. Activator protein-1 (AP-1), a transcription factor, is implicated in the transcriptional regulation of a wide range of genes participating in cell proliferation and ECM production. This investigation was undertaken to test the hypothesis that AP-1 plays an important role in ECM gene expression, and to develop a molecular therapeutic strategy based on decoy oligodeoxynucleotides (ODN). In this report, we show that transfection with AP-1 decoy ODN strongly inhibits high glucose-and angiotensin II-induced cell proliferation and expression of ECM genes in cultured mesangial cells in vitro. Administration of AP-1 decoy ODN into streptozotocin-induced diabetic rat kidney in vivo using the hemagglutinating virus of Japan (HVJ)-liposome method virtually abolished TGF-b1 and plasminogen activator inhibitor-1 expression. Our results collectively indicate that AP-1 activation is crucial for mesangial cell proliferation and ECM production in response to high glucose and angiotensin II. Moreover, use of stable AP-1 decoy ODN combined with the highly effective HVJliposome method provides a novel potential molecular therapeutic strategy for the prevention of diabetic nephropathy. Gene Therapy (2004) 11, 916-923.

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Section: Discussionmentioning

confidence: 99%

Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo

Ahn

Morishita²,

Kaneda³

et al. 2004

Gene Ther

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“…27,30 E2F decoy oligonucleotides have been shown to be capable of suppressing mesangial cell proliferation in vitro and in vivo. 31,32 ECM-induced cell cycle arrest in mesangial cells was shown to be associated with transcriptional repression of E2F-responsive genes such as c-myc, cyclin A and cdc2. 33 In contrast to these reports, we did not detect a corresponding upregulation of the protein products of E2F-responsive genes in the mesangium of glomeruli in human IgAN.…”

Section: Discussionmentioning

confidence: 99%

Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

Qiu

Sinniah

Hsu

2004

Laboratory Investigation

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The activities of cell cycle regulatory proteins have been reported to be associated with the development of pathological lesions in glomerulonephritis. To assess the cellular mechanisms underlying the mesangial cell proliferation and glomerulosclerosis in progressive human IgA nephropathy (IgAN), we examined the expression of E2F1, Rb, c-Myc, proliferating cell nuclear antigen (PCNA), cyclins (D1, E and A), cyclindependent kinase 2 (CDK2) and CDK inhibitors (p21 waf1 , p27 kip1 , 57 kip2 and p16 ink4a ) by immunohistochemistry in renal biopsy specimens. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was also performed to detect the presence of apoptosis. In total, 51 cases of IgAN were categorized into four subgroups according to histological severity. A dramatic upregulation of E2F1 expression in mesangial cells was identified in proliferating glomeruli, which correlated well with the proliferation index. High endogenous expression of p27 kip1 and p57 kip2 by podocytes in normal glomeruli and glomeruli with minor lesions was observed to decrease in proliferating and sclerosing glomeruli; this pattern displayed a strong inverse correlation with the mean glomerulosclerosis score and the index of glomerular lesion. Increased apoptotic activity was identified in progressive glomerular lesions of advanced IgAN, which correlated with the proliferative activity in these lesions as assessed by total expression levels of PCNA and CDK2 in glomeruli, E2F1 expression levels in the mesangium, cyclin D1 expression levels in endothelium and the c-Myc glomerular staining score. Our results suggest that the onset and magnitude of mesangial cell proliferation and glomerulosclerosis is associated with the upregulation of E2F1 by mesangial cells and the downregulation of p27 kip1 and p57 kip2 by glomerular epithelial cells. The cell type-specific and coordinated regulation of proliferative and proapoptotic activities of cell cycle regulatory proteins may play an important role in mediating progressive glomerular injury in human IgAN. Laboratory Investigation (2004) 84, 1112-1125, advance online publication, 21 June 2004 doi:10.1038/labinvest.3700144 Keywords: IgA nephropathy; cell cycle regulatory protein; mesangial cell proliferation; glomerulosclerosis; apoptosis Cell cycle regulatory proteins (CCPs) govern not only cellular hypertrophy and proliferation, but also cellular apoptosis and differentiation. Mounting evidence has emerged that indicates a close link between cell cycle regulation and the development of histopathological lesions in glomerular diseases. 1,2 In the experimental model of mesangial proliferative anti-Thy1.1 nephritis, increased expression of cyclins A, D1 and cyclin-dependent kinase 2 (CDK2) by mesangial cells in association with decreased high endogenous levels of CDK inhibitor (CKI) p27 kip1 by glomerular epithelial cells (GECs), were required for mesangial cell proliferation. [3][4][5] The increased glomerular activity of CDK2 could be inhibited by the CDK antagonist r...

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“…A number of strategies have been reported to successfully block either E2F-1 function or E2F DNA binding activity (Morishita et al, 1995;Ishizaki et al, 1996;Chiang et al, 1997Chiang et al, , 1998Bandara et al, 1997;Maeshima et al, 1998), and each has been shown to inhibit cell growth. Some of these have been tested as potential therapies for tumours or hyperproliferative diseases with promising results.…”

Section: Discussionmentioning

confidence: 99%

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

et al. 2000

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Squamous di erentiation of keratinocytes is associated with decreases in E2F-1 mRNA expression and E2F activity, and these processes are disrupted in squamous cell carcinoma cell lines. We now show that E2F-1 mRNA expression is increased in primary squamous cell carcinomas of the skin relative to normal epidermis. To explore the relationship between E2F-1 and squamous di erentiation further, we examined the e ect of altering E2F activity in primary human keratinocytes induced to di erentiate. Promoter activity for the proliferationassociated genes, cdc2 and keratin 14, are inhibited during squamous di erentiation. This inhibition can be inhibited by overexpression of E2F-1 in keratinocytes. Overexpression of E2F-1 also suppressed the expression of di erentiation markers (transglutaminase type 1 and keratin 10) in di erentiated keratinocytes. Blocking E2F activity by transfecting proliferating keratinocytes with dominant negative E2F-1 constructs inhibited the expression of cdc2 and E2F-1, but did not induce di erentiation. Furthermore, expression of the dominant negative construct in epithelial carcinoma cell lines and normal keratinocytes decreased expression from the cdc2 promoter. These data indicate that E2F-1 promotes keratinocyte proliferation-speci®c marker genes and suppresses squamous di erentiation-speci®c marker genes. Moreover, these data indicate that targeted disruption of E2F-1 activity may have therapeutic potential for the treatment of squamous carcinomas.

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Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo.

Cited by 82 publications

References 61 publications

Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo

Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo

Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

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