Treatment of Renal Fibrosis—Turning Challenges into Opportunities

Klinkhammer, Barbara M.; Goldschmeding, Roel; Floege, Jürgen; Boor, Peter

doi:10.1053/j.ackd.2016.11.002

Cited by 130 publications

(117 citation statements)

References 48 publications

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“…We have shown that inflammation is a key driver of further fibrosis, and that early use of anti‐inflammatory drugs, ergonomic task reduction and manual therapy treatments are able to prevent their development 5‐10 . However, treatments aimed at reducing established muscle and other tissue fibrosis have proved to be more difficult, 11‐14 because once deposited and cross‐linked, the extracellular matrix becomes resistant to degradation 15 . There is even evidence from studies examining fibrotic kidneys that fibroblasts collected from these fibrotic kidneys have undergone epigenetic alterations that render these cells chronically activated 16 .…”

Section: Introductionmentioning

confidence: 99%

Blocking CTGF/CCN2 reduces established skeletal muscle fibrosis in a rat model of overuse injury

et al. 2020

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Abbreviations: αSMA, alpha smooth muscle actin; BCA, bicinchoninic acid; CD45, leukocyte common antigen; CCN1/Cyr61, cellular communication network factor 1; also known as Cysteine-rich angiogenic inducer 61; CCN2, cellular communication network factor 2; also known as connective tissue growth factor, CTGF; CCN3/NOV, cellular communication network factor 3; also known as nephroblastoma overexpressed; Fsp1, fibroblast-specific growth factor 1; FG-3019, Pamrevlumab, an anti-CCN2 agent; FGF2/bFGF, fibroblast growth factor 2/basic fibroblast growth factor; FRC, food-restricted controls; gf, grams of force; HRH, high repetition high force; IgG, immunoglobulin; pERK, phosphorylated extracellular signal-related kinase; NK1RA, neurokinin 1 receptor antagonist; PINP, pro-collagen I intact N-terminal protein; PDGFRβ, platelet-derived growth factor receptor beta; PINP, Pro-collagen I intact N-terminal protein; SMA, smooth muscle actin; TGFβ1, transforming growth factor beta 1; vWC, von Willebrand factor type C domain. AbstractTissue fibrosis is a hallmark of overuse musculoskeletal injuries and contributes to functional declines. We tested whether inhibition of CCN2 (cellular communication network factor 2, previously known as connective tissue growth factor, CTGF) using a specific antibody (termed FG-3019 or pamrevlumab) reduces established overuseinduced muscle fibrosis in a clinically relevant rodent model of upper extremity overuse injury. Young adult rats performed a high repetition high force (HRHF) reaching and lever-pulling task for 18 weeks, after first being shaped for 6 weeks to learn this operant task. Rats were then euthanized (HRHF-Untreated), or rested and treated for 6 weeks with FG-3019 (HRHF-Rest/FG-3019) or a human IgG as a vehicle control (HRHF-Rest/ IgG). HRHF-Untreated and HRHF-Rest/IgG rats had higher muscle levels of several fibrosis-related proteins (TGFβ1, CCN2, collagen types I and III, and FGF2), and higher muscle numbers of alpha SMA and pERK immunopositive cells, compared to control rats. Each of these fibrogenic changes was restored to control levels by the blocking of CCN2 signaling in HRHF-Rest/FG-3019 rats, as were HRHF task-induced increases in serum CCN2 and pro-collagen I intact N-terminal protein. Levels of cleaved CCN3, an antifibrotic protein, were lowered in HRHF-Untreated and HRHF-Rest/IgG rats, compared to control rats, yet elevated back to control levels in HRHF-Rest/FG-3019 rats. Significant grip strength declines observed in HRHF-Untreated and HRHF-Rest/ IgG rats, were restored to control levels in HRHF-Rest/FG-3019 rats. These results are highly encouraging for use of FG-3019 for therapeutic treatment of persistent skeletal muscle fibrosis, such as those induced with chronic overuse. K E Y W O R D SCCN2, extracellular matrix, overuse injury, TGF-beta, work-related musculoskeletal disorders | 6555 BARBE Et Al. F I G U R E 1 Design of experiment. Young adult female Sprague Dawley rats were randomly divided into one of four groups: age-and weightmatched food-restricted controls (F...

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Section: Introductionmentioning

confidence: 99%

Blocking CTGF/CCN2 reduces established skeletal muscle fibrosis in a rat model of overuse injury

et al. 2020

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“…2 Until now, the efficacy of current strategies available for inhibiting or reversing renal brosis remains unsatisfactory. 3,4 Transforming growth factor b1 (TGF-b1) is known as a key pro-brotic factor in renal brosis. 5,6 During development of renal brosis, TGF-b1 can induce myobroblastic activation and abundant deposition of collagen and bronectin in renal tubulointerstitium.…”

Section: Introductionmentioning

confidence: 99%

Retracted Article: TMEM88 inhibits fibrosis in renal proximal tubular epithelial cells by suppressing the transforming growth factor-β1/Smad signaling pathway

Wang

Chen

et al. 2019

RSC Adv.

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Transmembrane protein 88 (TMEM88) belongs to a member of the TMEM family, and was reported to be involved in fibrogenesis. However, the biological role of TMEM88 in renal fibrosis has not been elucidated. Therefore, the objective of this study was to investigate the effect of TMEM88 on cell proliferation and extracellular matrix (ECM) accumulation in a TGF-b1-induced human renal proximal tubular epithelial cell line (HK2). Our results showed that TMEM88 was downregulated in renal fibrotic tissues and TGF-b1-treated HK2 cells. In addition, TMEM88 overexpression inhibited TGF-b1-induced cell proliferation and migration in HK2 cells. Furthermore, TMEM88 overexpression reduced the production of a-SMA, collagen I, and collagen III in TGF-b1-stimulated HK2 cells. Mechanistically, TMEM88 overexpression suppressed the phosphorylation status of Smad2 and Smad3 in TGF-b1-stimulated HK2 cells. In conclusion, data from our experiments demonstrate that TMEM88 plays a pivotal role in the pathological process of renal fibrosis. TMEM88 inhibited fibrosis in renal proximal tubular epithelial cells by suppressing the TGF-b1/Smad signaling pathway. Cell cultureHuman renal proximal tubular epithelial cell line (HK2) was obtained from the American Type Cell Collection (ATCC,

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“…the synthesis and excess deposition of extracellular matrix causing increased stiffness and loss in the function of renal tubules. 3,4 Since there are promising results that demonstrate the potential to curb renal fibrosis and even reverse it, 5,6 significant advances in diagnosing renal fibrosis are warranted.…”

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confidence: 99%

Magnetic Resonance Elastography of kidneys: SE‐EPI MRE reproducibility and its comparison to GRE MRE

et al. 2019

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The purpose of this study is 1) to demonstrate reproducibility of spin echo‐echo planar imaging (SE‐EPI) magnetic resonance elastography (MRE) to estimate kidney stiffness; and 2) to compare SE‐EPI MRE and gradient recalled echo (GRE) MRE‐derived stiffness estimations in various anatomical regions of the kidney. Kidney MRE was performed on 33 healthy subjects (8 for SE‐EPI MRE reproducibility and 25 for comparison with GRE MRE; age range: 22–66 years) in a 3 T MRI scanner. To demonstrate SE‐EPI MRE reproducibility, subjects were scanned for the first scan and then asked to leave the scan room and repositioned again for the second (repeat) scan. Similar set‐up was used for GRE MRE as well. The displacement data was then processed to obtain overall stiffness estimates of the kidney. Concordance correlation analyses were performed to determine SE‐EPI MRE reproducibility and agreement between GRE MRE and SE‐EPI MRE derived stiffness. A high concordance correlation (ρc = 0.95; p‐value<0.0001) was obtained for SE‐EPI MRE reproducibility. Good concordance correlation was observed (ρc = 0.84; p < 0.0001 for both kidneys, ρc = 0.91; p < 0.0001 for right kidney and ρc = 0.78; p < 0.0001 for left kidney) between GRE MRE and SE‐EPI MRE derived stiffness measurements. Paired t‐test results showed that stiffness value of medulla was significantly (p < 0.0001) greater than cortex using SE‐EPI MRE as well as GRE MRE. SE‐EPI MRE was reproducible and good agreement was observed in MRE‐derived stiffness measurements obtained using SE‐EPI and GRE sequences. Therefore, SE‐EPI can be used for kidney MRE applications.

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Treatment of Renal Fibrosis—Turning Challenges into Opportunities

Cited by 130 publications

References 48 publications

Blocking CTGF/CCN2 reduces established skeletal muscle fibrosis in a rat model of overuse injury

Blocking CTGF/CCN2 reduces established skeletal muscle fibrosis in a rat model of overuse injury

Retracted Article: TMEM88 inhibits fibrosis in renal proximal tubular epithelial cells by suppressing the transforming growth factor-β1/Smad signaling pathway

Magnetic Resonance Elastography of kidneys: SE‐EPI MRE reproducibility and its comparison to GRE MRE

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