C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease

Li, Ling; Chen, Lijia; Zang, Jing; Tang, Xi; Liu, Yan; Zhang, Jie; Bai, Lin; Yin, Qudong; Liu, Yanrong; Cheng, Jun; Fu, Ping; Liu, Fang

doi:10.1016/j.metabol.2015.01.014

Cited by 125 publications

(103 citation statements)

References 34 publications

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“…Importantly, in the glomeruli of both WT and C fh −/− mice with protein-overload the presence of C3a -an active fragment generated when C3 convertase cleaves C3 in C3b-coupled to the increased expression of C3aR by podocytes and PECs may locally contribute to amplify cell injury. In this context, the relevance of C3a/C3aR axis has been documented as a part of a novel mechanism of renal fibrosis and glomerular sclerosis in animals and patients with diabetic nephropathy5657.…”

Section: Discussionmentioning

confidence: 99%

“…However, targeted C3 inhibition often raised the concern that a completely shut down of C3 activity could increase susceptibility to infections. Other complement regulator-based approaches blocking the activation of C3 via the AP, such as TT30 (CR2- FH fusion protein) and mini-FH58, as well as C3a receptor antagonists, tested in preclinical studies5657 could offer the advantage of avoiding the adverse effects, providing unprecedent opportunities for long-term systemic interventions.…”

Section: Discussionmentioning

confidence: 99%

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A previously unrecognized role of C3a in proteinuric progressive nephropathy

Morigi

Locatelli

Rota

et al. 2016

Sci Rep

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Podocyte loss is the initial event in the development of glomerulosclerosis, the structural hallmark of progressive proteinuric nephropathies. Understanding mechanisms underlying glomerular injury is the key challenge for identifying novel therapeutic targets. In mice with protein-overload induced by bovine serum albumin (BSA), we evaluated whether the alternative pathway (AP) of complement mediated podocyte depletion and podocyte-dependent parietal epithelial cell (PEC) activation causing glomerulosclerosis. Factor H (Cfh−/−) or factor B-deficient mice were studied in comparison with wild-type (WT) littermates. WT+BSA mice showed podocyte depletion accompanied by glomerular complement C3 and C3a deposits, PEC migration to capillary tuft, proliferation, and glomerulosclerosis. These changes were more prominent in Cfh−/− +BSA mice. The pathogenic role of AP was documented by data that factor B deficiency preserved glomerular integrity. In protein-overload mice, PEC dysregulation was associated with upregulation of CXCR4 and GDNF/c-Ret axis. In vitro studies provided additional evidence of a direct action of C3a on proliferation and CXCR4-related migration of PECs. These effects were enhanced by podocyte-derived GDNF. In patients with proteinuric nephropathy, glomerular C3/C3a paralleled PEC activation, CXCR4 and GDNF upregulation. These results indicate that mechanistically uncontrolled AP complement activation is not dispensable for podocyte-dependent PEC activation resulting in glomerulosclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A previously unrecognized role of C3a in proteinuric progressive nephropathy

Morigi

Locatelli

Rota

et al. 2016

Sci Rep

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“…Despite these observations very few studies have examined the role of Wnt pathway activation on the generation of activated myofibroblasts through EndoMT. Two recent studies demonstrated that induction of canonical Wnt signaling resulted in EndoMT pathway activation in cultured EC and in myocardial EC following experimentally-induced myocardial infarction and in human renal glomerular EC cultured in a high glucose medium [97,98]. In contrast, one study showed that the Wnt inhibitor Dkk-1 enhanced EndoMT in aortic EC [99] results that indicate that further study is needed to conclusively determine the precise role of Wnt and of its inhibition on EndoMT-induced myofibroblast generation.…”

Section: Roles Of Pathways Involved In Ssc Pathogenesis In the Molecumentioning

confidence: 99%

Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of Systemic Sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality?

Jimenez

Piera-Velázquez

2016

Matrix Biology

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Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and multiple internal organs and severe functional and structural microvascular alterations. SSc is considered to be the prototypic systemic fibrotic disorder. Despite currently available therapeutic approaches SSc has a high mortality rate owing to the development of SSc-associated interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), complications that have emerged as the most frequent causes of disability and mortality in SSc. The pathogenesis of the fibrotic process in SSc is complex and despite extensive investigation the exact mechanisms have remained elusive. Myofibroblasts are the cells ultimately responsible for tissue fibrosis and fibroproliferative vasculopathy in SSc. Tissue myofibroblasts in SSc originate from several sources including expansion of quiescent tissue fibroblasts and tissue accumulation of CD34+ fibrocytes. Besides these sources, myofibroblasts in SSc may result from the phenotypic conversion of endothelial cells into activated myofibroblasts, a process known as endothelial to mesenchymal transition (EndoMT). Recently, it has been postulated that EndoMT may play a role in the development of SSc-associated ILD and PAH. However, although several studies have described the occurrence of EndoMT in experimentally induced cardiac, renal, and pulmonary fibrosis and in several human disorders, the contribution of EndoMT to SSc-associated ILD and PAH has not been generally accepted. Here, the experimental evidence supporting the concept that EndoMT plays a role in the pathogenesis of SSc-associated ILD and PAH will be reviewed.

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“…ET-1 activates the ET A R/NADPH oxidase pathway or Wnt/β-catenin pathway and decreases the antioxidant activity by increasing oxidative stress, which promotes endothelial progenitor cell apoptosis and dysfunction [73,74]. Therefore, the interaction between endothelin and aldosterone, together with the regulation of inflammation, oxidative stress and fibrosis participate in the development of DKD.…”

Section: Accepted Manuscriptmentioning

confidence: 99%