CD44v3-v10 reduces the profibrotic effects of TGF-β1 and attenuates tubular injury in the early stage of chronic obstructive nephropathy

Rampanelli, Elena; Rouschop, Kasper M.A.; Teske, Gwendoline J. D.; Claessen, Nike; Leemans, Jaklien C.; Florquin, Sandrine

doi:10.1152/ajprenal.00340.2013

Cited by 8 publications

(9 citation statements)

References 68 publications

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“…For example, DNA methylation changes may be important in BMP7 activity since the prevention of kidney fibrosis was linked to the reversal of Rasal1 promoter hypermethylation (Tampe et al, 2014). In another study, changes in the expression of specific receptors on tubular epithelial cells (e.g., CD44v3) resulted in enhanced BMP7 synthesis and an associated reduction of renal fibrotic damage (Rampanelli et al, 2013). Also, the protective role of BMP7 was shown to be related to changes in the expression of miRNAs as the suppression of miR-21 in rat kidney cells was found to associate with BMP7-mediated inhibition of fibronectin secretion and apoptosis (Yu et al, 2016).…”

Section: The Antifibrotic Therapeutic Role Of Bmp7mentioning

confidence: 99%

Novel Anti-fibrotic Therapies

McVicker

Bennett

2017

Front. Pharmacol.

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Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Novel treatments have recently been identified that hold promise as potential therapeutic agents for cardiovascular diseases associated with fibrosis, as well as other fibrotic conditions. The purpose of this review is to provide an overview of emerging antifibrotic agents that have shown encouraging results in preclinical or early clinical studies, but have not yet been approved for use in human disease. One of these agents is bone morphogenetic protein-7 (BMP7), which has beneficial effects in multiple models of fibrotic disease. Another approach discussed involves altering the levels of micro-RNA (miR) species, including miR-29 and miR-101, which regulate the expression of fibrosis-related gene targets. Further, the antifibrotic potential of agonists of the peroxisome proliferator-activated receptors will be discussed. Finally, evidence will be reviewed in support of the polypeptide hormone relaxin. Relaxin is long known for its extracellular remodeling properties in pregnancy, and is rapidly emerging as an effective antifibrotic agent in a number of organ systems. Moreover, relaxin has potent vascular and renal effects that make it a particularly attractive approach for the treatment of cardiovascular diseases. In each case, the mechanism of action and the applicability to various fibrotic diseases will be discussed.

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Section: The Antifibrotic Therapeutic Role Of Bmp7mentioning

confidence: 99%

Novel Anti-fibrotic Therapies

McVicker

Bennett

2017

Front. Pharmacol.

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“…Fibroblast activation and proliferation are triggered by locally secreted fibrogenic cytokines such as TGF-β1, connective tissue growth factor, and monocyte chemotactic protein-1 (MCP-1) [55,56]. Among these fibrogenic cytokines, TGF-β signaling initiates renal tubular cell proapoptotic effects and the epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells.…”

Section: Renoprotective Mechanisms Of Vitamin D In Experimental Studiesmentioning

confidence: 99%

Vitamin D and chronic kidney disease

Kim

2014

Korean J Intern Med

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Chronic kidney disease (CKD) has been recognized as a significant global health problem because of the increased risk of total and cardiovascular morbidity and mortality. Vitamin D deficiency or insufficiency is common in patients with CKD, and serum levels of vitamin D appear to have an inverse correlation with kidney function. Growing evidence has indicated that vitamin D deficiency may contribute to deteriorating renal function, as well as increased morbidity and mortality in patients with CKD. Recent studies have suggested that treatment with active vitamin D or its analogues can ameliorate renal injury by reducing fibrosis, apoptosis, and inflammation in animal models; this treatment also decreases proteinuria and mortality in patients with CKD. These renoprotective effects of vitamin D treatment are far beyond its classical role in the maintenance of bone and mineral metabolism, in addition to its pleiotropic effects on extra-mineral metabolism. In this review, we discuss the altered metabolism of vitamin D in kidney disease, and the potential renoprotective mechanisms of vitamin D in experimental and clinical studies. In addition, issues regarding the effects of vitamin D treatment on clinical outcomes are discussed.

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“…Immunohistochemistry, collagen assay, ELISA, and immunoblotting Renal tissues were fixed in 10% formalin for 24 h and subsequently embedded in paraffin in a routine manner. All stainings were performed as previously described 3,16 on paraffin sections, except for phosphorylated c-Met and phosphorylated-Smad-2/3 (frozen sections). All histopathological scorings were made in the cortex and performed in a blinded manner.…”

Section: Mice and Experimental Protocolmentioning

confidence: 99%

“…All histopathological scorings were made in the cortex and performed in a blinded manner. 3,16 Tubular injury was assessed by grading tubular dilatation, epithelial simplification, and brush border loss in 10 randomly chosen, nonoverlapping fields (Â20 magnification). Proliferation and apoptosis were assessed by counting BrdU-positive TECs per 1000 TECs and active-caspase-3positive TECs per mm 2 , respectively.…”

Section: Mice and Experimental Protocolmentioning

confidence: 99%

“…Recent reports highlighted the importance of CD44s in TGF-b1-mediated epithelial-to-mesenchymal transition, 14,15 and our earlier study showed that CD44s expression by tubular epithelial cells (TECs) sensibilizes cells to TGFb-1 profibrotic effects. 16 Another isoform of CD44 that has been extensively studied is CD44-variant-3 (CD44v3/CD44v3-v10), which contains variable exons 3-10 and has heparan sulfate (HS) chains attached to its extracellular domain. Owing to the HS chains, CD44v3 is capable of binding growth factors containing an HS-binding site, such as the renoprotective HGF, and facilitates the cross-linking with their receptors.…”

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confidence: 99%

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Opposite role of CD44-standard and CD44-variant-3 in tubular injury and development of renal fibrosis during chronic obstructive nephropathy

Rampanelli

Rouschop

Claessen

et al. 2014

Kidney International

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Chronic kidney diseases (CKDs) are characterized by tubular atrophy and interstitial fibrosis. We previously showed that in obstructive nephropathy de novo CD44 renal expression contributes to renal fibrosis but attenuates tubular damage/apoptosis. As CD44-standard (CD44s) has been linked to TGF-β1-mediated actions and CD44-variant-3 (CD44v3) favors HGF-c-Met binding, we compared the functional properties of these CD44 isoforms in the progression of obstructive nephropathy, using specific CD44-variant knockout/knockin mice. The presence of CD44v3 diminished tubular damage during obstructive nephropathy, decreased apoptosis, and increased proliferation of tubular epithelial cells, and prevented renal fibrosis development. In contrast, expression of CD44s led to increased tubular damage and tubular epithelial cell apoptosis, and more renal fibrosis. A relative increase in renal β-catenin expression, HGF production, and HGF/c-Met signaling, together with a relative inhibition of TGF-β1 downstream signaling and TGF-β type I receptor expression, was found in CD44v3 mice compared with CD44s littermates. In line with this, Wnt3a/HGF treatment of tubular cells resulted in higher β-catenin/p-AKT levels in CD44v3(+) tubular epithelial cells, whereas TGF-β1 induced a mild collagen I upregulation in CD44v3(+) mouse embryonic fibroblasts as compared with CD44s(+) cells. Thus, CD44s and CD44v3 exert opposite roles in the progression of obstructive nephropathy, with CD44v3-v10 being the protective isoform that delays evolution of the renal pathology.

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CD44v3-v10 reduces the profibrotic effects of TGF-β1 and attenuates tubular injury in the early stage of chronic obstructive nephropathy

Abstract: Rampanelli E, Rouschop K, Teske GJ, Claessen N, Leemans JC, Florquin S. CD44v3-v10 reduces the profibrotic effects of TGF-␤1 and attenuates tubular injury in the early stage of chronic obstructive nephropathy.

Cited by 8 publications

References 68 publications

Novel Anti-fibrotic Therapies

Novel Anti-fibrotic Therapies

Vitamin D and chronic kidney disease

Opposite role of CD44-standard and CD44-variant-3 in tubular injury and development of renal fibrosis during chronic obstructive nephropathy

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