Reduction in Connective Tissue Growth Factor by Antisense Treatment Ameliorates Renal Tubulointerstitial Fibrosis

Yokoi, Hideki; Mukoyama, Masashi; Nagae, Tetsuya; Mori, Kiyoshi; Suganami, Takayoshi; Sawai, Kenji; Yoshioka, Takakazu; Koshikawa, Masao; Nishida, Takashi; Takigawa, Masaharu; Sugawara, Akira; Nakao, Kazuwa

doi:10.1097/01.asn.0000130565.69170.85

Cited by 226 publications

(225 citation statements)

References 51 publications

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“…2,12 Antagonists of CCN2 have proven effective in blocking profibrogenic CCN2 signaling pathways in vitro and have yielded promising data with respect to preventing experimental fibrosis. 14 Regarding renal diseases, knockdown of CCN2 gene expression with antisense gene transfer into rat kidney ameliorates tubulointerstitial fibrosis in obstructive nephropathy 14 and in experimental mice diabetes in C57BL/6 mice. 16 CCN2 is known to function downstream of TGF-b, driving extracellular matrix accumulation and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…2,12 The concept of CCN2 as a downstream mediator of profibrotic factors, including transforming growth factor-b (TGF-b) and Angiotensin II, is the chief operating paradigm in the field. 13,14 Therapeutic approaches that selectively block endogenous CCN2 activity have proven beneficial effects in fibrotic-related diseases, including experimental lung, liver, vascular, and renal diseases, and some authors have suggested that CCN2 could be a therapeutic target for fibrosis. [12][13][14][15][16] However, cardiac CCN2 overexpression conferred cardioprotection in Angiotensin II-infused mice and in ischemia-reperfusion injury, 17,18 showing that CCN2 exerts protective effects in some pathological settings.…”

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confidence: 99%

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The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

Rodrigues‐Díez

Rodrigues-Díez

Rayego‐Mateos

et al. 2013

Laboratory Investigation

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

Rodrigues‐Díez

Rodrigues-Díez

Rayego‐Mateos

et al. 2013

Laboratory Investigation

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“…Overnight microalbumin (nephelometry)/Cr ratios (mg/g) (mean ϮSD) at days 0 (baseline), 56 (2 weeks after final infusion), and 84 (during washout period) (efficacy population) primarily in podocytes, (6) and the development of more severe DKD in mice overexpressing CTGF specifically in podocytes (47). Heterozygous CTGF knockout (Ϯ) mice developed less severe albuminuria and glomerular basement membrane thickening with diabetes (48), and a CTGF antisense oligonucleotide decreased albuminuria, mesangial hypertrophy, and the increased serum Cr in murine models (streptozotocin and db/db) of type 1 and 2 diabetes (49).…”

Section: Discussionmentioning

confidence: 99%

Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria

Adler¹,

Schwartz²,

Williams³

et al. 2010

Clinical Journal of the American Society of Nephrology

188

103

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Background and objectives: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins.Design, setting, participants, and measurements: Microalbuminuric subjects (n ‫؍‬ 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively.Results: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P ‫؍‬ 0.027) without evidence for a dose-response relationship.Conclusions: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.

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“…Recently, Yokoi et al (35) used antisense ODN technology to demonstrate that CTGF expression in interstitial cells played an important role in interstitial fibrogenesis in the unilateral ureteral obstruction model. Their findings, coupled with ours, support the notion that CTGF acts as an important profibrotic mediator of TGF-␤'s effects in the renal tubulointerstitium while not eliminating the possibility that it plays a similar role in the glomerulus.…”

Section: Discussionmentioning

confidence: 99%

Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis

Okada

Kikuta

Kobayashi

et al. 2005

Journal of the American Society of Nephrology

166

145

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Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-␤. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-␤1-induced CTGF. In these co-cultures, TGF-␤1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. C onnective tissue growth factor (CTGF) is a 38-kD cysteine-rich peptide that belongs to the emerging CCN (CTGF, cyr 61/cef 10, nov) family of multifunctional growth factors (1-4). Murine CTGF, which is also called fisp-12, promotes chemotaxis, migration, adhesion, proliferation, and differentiation or formation of the extracellular matrix (ECM), depending on whether the target cell is a fibroblast, chondrocyte, or vascular endothelial cell (2). CTGF is induced exclusively by TGF-␤ and is thought to mediate the latter's profibrotic effects by modulating fibroblast cell growth and ECM protein synthesis (1,4). CTGF expression has been shown to increase in a variety of human diseases and experimental disease models that are characterized by fibrosis, including those that affect the kidney, skin, blood vessels, lung, and liver (1,2). In the case of the kidney, CTGF mRNA was shown to be expressed primarily in glomerular mesangial, epithelial, and endothelial cells in IgA nephropathy, focal and segmental glomerulosclerosis, and diabetic nephropathy (5,6). Moreover, CTGF mRNA overexpression was found in tubular epithelial cells and interstitial cells at sites of chronic interstitial damage (5,6). In the remnant kidney of the subtotal nephrectomy (SNx) model and in the kidneys with ureteral obstruction, tubular CTGF was shown to be expressed in response to renal interstitial fibrosis (7,8). These findings strongly suggest that renal interstitial fibrogenesis is mediated by CTGF that is expressed in the tubular epithelial cells. However, whether CTGF plays a direct role in vivo in renal interstitial fibrogenesis remains to be elucidated. In the present study, we demonstrated, using neutralization protocols, that tubular CTGF directly and significantly contributed to TGF-␤1-dependent renal interstitial fibrogenesis. Materials and Methods CTGF Antisense OligodeoxynucleotidesPhosphorothioate-capped oligodeoxynucleotides (ODN) were synthesized by an automated synthesizer. After deprotection, ODN were dissolved in water, extracted with phenol/chloroform/isoamyl alco-

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Reduction in Connective Tissue Growth Factor by Antisense Treatment Ameliorates Renal Tubulointerstitial Fibrosis

Cited by 226 publications

References 51 publications

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria

Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis

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