Electroporation-mediated PDGF receptor-IgG chimera gene transfer ameliorates experimental glomerulonephritis

Nakamura, Hiroyuki; Isaka, Yoshitaka; Tsujie, Michiko; Akagi, Yuya; Sudo, Tetsuo; Ohno, Noriko; Imai, Enyu; Hori, Masatsugu

doi:10.1046/j.1523-1755.2001.0590062134.x

Cited by 22 publications

(23 citation statements)

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“…No damage was observed in the kidney from this procedure. Second, it is rather simple because it does not require special techniques such as electroporation (40). It is therefore theoretically possible to apply this method to the human kidney by using proper catheters.…”

Section: Discussionmentioning

confidence: 99%

Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Renal Injury Induced by Protein-Overload Proteinuria

Shimizu¹,

Maruyama²,

Yuzawa³

et al. 2003

Journal of the American Society of Nephrology

121

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Abstract. It has been postulated that protein filtered through glomeruli activates tubular epithelial cells, which secrete vasoactive and inflammatory substances including chemokines, leading to tubulointerstitial renal injury. The present study was designed to investigate the role of monocyte chemoattractant protein-1 (MCP-1) in this process and to evaluate the effectiveness of a kidney-targeted gene transfer technique using hydrodynamic pressure. Naked plasmid encoding 7ND (an MCP-1 antagonist) or a control plasmid was introduced into the left kidney of rats. Three days after gene transfer (day 0), intraperitoneal administration of bovine serum albumin (10 mg/g body wt per day) was started and continued for 14 or 21 d. RT-PCR showed that 7ND mRNA was expressed only in the gene-transfected kidney. Immunostaining showed that 7ND protein was localized in the interstitial cells. Macrophage infiltration was significantly reduced in the left kidney of rats treated with 7ND on days 14 and 21. In the right kidney, such effects were not observed. 7ND also attenuated tubular damage and decreased the number of apoptotic cells. Computer-assisted analysis revealed that the areas positively stained for ␣-smooth muscle actin (␣SMA), fibronectin-EDA, type I collagen, and collagen fibrils were significantly reduced in the 7ND-treated kidney on day 21. Furthermore, 7ND gene therapy significantly reduced MCP-1 and TGF-␤1 mRNA expression. These results demonstrate that MCP-1 plays an important role in the development of tubulointerstitial inflammation, tubular damage, and fibrosis induced by proteinuria. The fact that 7ND gene therapy had little effect on the contralateral kidney indicates that 7ND acted locally. This strategy may have a potential usefulness as a gene therapy against tubulointerstitial renal injury.Besides being a hallmark of glomerular disease, proteinuria has been shown to be an independent factor that induces and maintains renal damage. Cellular infiltration and fibrosis in the interstitium are common characteristics for virtually all progressive renal diseases with proteinuria. It has been postulated that protein filtered through glomeruli activates tubular epithelial cells, induces cellular infiltration into the interstitium, and subsequently causes interstitial fibrosis (1). Secretion of vasoactive mediators (e.g., endothelins), and chemokines, (e.g., monocyte chemoattractant protein-1 [MCP-1] and osteopontin) are induced in the tubules by protein-overload proteinuria (2,3). These substances are considered to promote inflammation and fibrosis of the interstitium, resulting in renal scarring (4,5). From among these mediators, we focused on MCP-1, a C-C chemokine with potent monocyte chemotactic and activating properties. It has been shown that MCP-1 is upregulated in various experimental and human renal diseases (6,7). MCP-1 expression is enhanced in tubular cells by bovine serum albumin (BSA) via a NF-B-dependent pathway (8). MCP-1 can also induce fibrosis through recruitment and activation of macrophages t...

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Section: Discussionmentioning

confidence: 99%

Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Renal Injury Induced by Protein-Overload Proteinuria

Shimizu¹,

Maruyama²,

Yuzawa³

et al. 2003

Journal of the American Society of Nephrology

121

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“…Besides its proliferative effects, PDGF recruits fibroblasts to sites of tissue injury. Experiments inhibiting the actions of PDGF have until now been limited to the anti-Thy 1 model in rats [10,[62][63][64][65]. In an early phase of the disease, the mesangial cell population is eliminated by mesangiolysis.…”

Section: Eikmans Et Almentioning

confidence: 99%

ECM homeostasis in renal diseases: a genomic approach

Eikmans

Baelde

Heer

et al. 2003

The Journal of Pathology

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Chronic renal disease is in general histologically accompanied by a vast amount of scar tissue, ie glomerulosclerosis and interstitial fibrosis. Scarring results from excessive accumulation of extracellular matrix (ECM) components, a process driven by a plethora of cytokines and growth factors. Studies in experimental renal disease which target these regulators using gene therapy limit or prevent the development of scarring. This review focuses specifically on the role of transforming growth factor-beta, platelet-derived growth factor, connective tissue growth factor, hepatocyte growth factor, and epidermal growth factor. The results obtained in animal models hold promise for molecular intervention strategies in human renal disease. Microarray technology allows large-scale gene expression profiling in kidney tissue to identify common molecular pathways in a step towards discovery of new drug targets. Molecular techniques are expected to be used for diagnostic and prognostic purposes in nephrological practice to supplement renal biopsy. Several studies already show that molecular techniques might be of use in routine diagnostic practice. Improvement of diagnosis and prediction of outcome in renal patients might lead to more efficient and earlier therapeutic intervention.

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“…Ample evidence is now available to link the PDGF system, in particular PDGF-B-chain, to both of these processes given that (1) mesangial cells produce PDGF-B in vitro and various growth factors induce mesangial proliferation via induction of auto-or paracrine PDGF-B-chain excretion (9 -12); (2) PDGF-B-chain and its receptor are overexpressed in many glomerular diseases (13)(14)(15)(16)(17); (3) infusion of PDGF-BB or glomerular transfection with a PDGF-B-chain cDNA can induce selective mesangial cell proliferation and matrix accumulation in vivo (18,19); (4) PDGF-Bchain or ␤-receptor knockout mice fail to develop a mesangium (20,21); and (5) specific inhibition of PDGF-B using antibodies, aptamers, soluble PDGF receptors, or PDGF ␤-receptor tyrosine kinase blockers not only results in a diminution of mesangiopro-liferative changes (reviewed in (1) and (22)(23)(24)) but, more important, was also able to prevent long-term renal scarring (25). Apart from its role in glomerular pathology, PDGF-B-chain may also contribute to renal interstitial fibrosis, i.e., the common final pathway of almost all progressive renal diseases.…”

mentioning

confidence: 99%

A Fully Human Monoclonal Antibody (CR002) Identifies PDGF-D as a Novel Mediator of Mesangioproliferative Glomerulonephritis

Ostendorf¹,

Roeyen²,

Peterson³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. PDGF-B is of central importance in mesangioproliferative diseases. PDGF-D, a new PDGF isoform, like PDGF-B, signals through the PDGF ␤␤-receptor. The present study first determined that PDGF-D is mitogenic for rat mesangial cells and is not inhibited by a PDGF-B antagonist. Low levels of PDGF-D mRNA were detected in normal rat glomeruli. After induction of mesangioproliferative nephritis in rats by anti-Thy 1.1 mAb, glomerular PDGF-D mRNA and protein expression increased significantly from days 4 to 9 in comparison with nonnephritic rats. Peak expression of PDGF-D mRNA occurred 2 d later than peak PDGF-B mRNA expression. In addition, PDGF-D serum levels increased significantly in the nephritic animals on day 7. For investigating the functional role of PDGF-D, neutralizing fully human mAb were generated using the XenoMouse technology. Rats with anti-Thy 1.1-induced nephritis were treated on days 3 and 5 with different amounts of a fully human PDGF-DDspecific neutralizing mAb (CR002), equal amounts of irrelevant control mAb, or PBS by intraperitoneal injection. Specific antagonism of PDGF-D led to a dose-dependent (up to 67%) reduction of glomerular cell proliferation. As judged by double immunostaining for 5-bromo-2'-deoxyuridine and ␣-smooth muscle actin, glomerular mesangial cell proliferation was reduced by up to 57%. Reduction of glomerular cell proliferation in the rats that received CR002 was not associated with reduced glomerular expression of PDGF-B mRNA. PDGF-D antagonism also led to reduced glomerular infiltration of monocytes/macrophages (day 5) and reduced accumulation of fibronectin (day 8). In contrast, no effect was noted in normal rats that received an injection of CR002. These data show that PDGF-D is overexpressed in mesangioproliferative states and can act as an auto-, para-, or even endocrine glomerular cell mitogen, indicating that antagonism of PDGF-D may represent a novel therapeutic approach to mesangioproliferative glomerulonephritides.

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Electroporation-mediated PDGF receptor-IgG chimera gene transfer ameliorates experimental glomerulonephritis

Abstract: These results suggest that gene therapy by the manipulation of PDGF action using electroporation-mediated PDGFR/Fc gene transfer to the skeletal muscle might be a useful treatment for mesangioproliferative glomerulonephritis.

Cited by 22 publications

References 0 publications

Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Renal Injury Induced by Protein-Overload Proteinuria

Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Renal Injury Induced by Protein-Overload Proteinuria

ECM homeostasis in renal diseases: a genomic approach

A Fully Human Monoclonal Antibody (CR002) Identifies PDGF-D as a Novel Mediator of Mesangioproliferative Glomerulonephritis

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