Dickkopf-3 in aberrant endothelial secretome triggers renal fibroblast activation and endothelial–mesenchymal transition

Lipphardt, Mark; Dihazi, Hassan; Jeon, Noo Li; Dadafarin, Sina; Ratliff, Brian B.; Rowe, David W.; Müller, Gerhard A.; Goligorsky, Michael S.

doi:10.1093/ndt/gfy100

“…It was concluded that the secretome partly mediates protection from LPS-induced AKI. Later studies showed that endothelium-derived humoral factors are also involved in renal fibrogenesis [25]. In the 2015 published article [24] In the last paragraph will would like to discuss our proteomic data.…”

Section: Discussionmentioning

confidence: 98%

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

Dihazi

¹

,

Schwarze

²

,

Patschan

³

et al. 2020

Preprint

0

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Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on so-called Proangiogenic Cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production / secretion of extracellular vesicles (MV -microvesicles). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived MV and / or the secretome alone. AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI -40 minutes). Syngeneic murine PACs were stimulated with either melatonine, Angiopoietin-1 or -2, or with Bone Morphogenetic Protein-5 (BMP-5) for one hour, respectively. PACderived MV and the vesicle-depleted supernatant were subsequently collected and i.v. injected postischemia. Mice were analyzed 48 hours later. IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of MV, collected from native PACs. The following conditions worsened post-ischemic renal function even further: MV+Ang-1, MV+BMP-5, MV+melatonin, and MV+secretome+Ang-1. Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived MV. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection.

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“…It was concluded that the secretome partly mediates protection from LPS-induced AKI. Later studies showed that endothelium-derived humoral factors are also involved in renal fibrogenesis [25]. In the 2015 published article [24] one essential problem related to any cell-based therapeutic approach in AKI was emphasized: the problem of cell delivery.…”

Section: Discussionmentioning

confidence: 99%

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

Dihazi¹,

Schwarze²,

Patschan³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on so-called Proangiogenic Cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production / secretion of extracellular vesicles (MV -microvesicles). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived MV and / or the secretome alone. AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI -40 minutes). Syngeneic murine PACs were stimulated with either melatonine, Angiopoietin-1 or -2, or with Bone Morphogenetic Protein-5 (BMP-5) for one hour, respectively. PACderived MV and the vesicle-depleted supernatant were subsequently collected and i.v. injected postischemia. Mice were analyzed 48 hours later. IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of MV, collected from native PACs. The following conditions worsened post-ischemic renal function even further: MV+Ang-1, MV+BMP-5, MV+melatonin, and MV+secretome+Ang-1. Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived MV. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection.

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“…Similarly, proximal tubules with tamoxifen-induced Wnt1 expression have profound interstitial myofibroblast activation and proliferation and increased extracellular matrix proteins production ( Maarouf et al, 2016 ). We showed that DKK3 is able to convert fibroblasts into myofibroblasts with DKK3 being secreted by SIRT1 deficient endothelial cells ( Lipphardt et al, 2018a ). We also investigated the relations between DKK1 and DKK3 and learned that DKK3 is only able to activate fibroblasts to acquire myofibroblastic phenotype at low levels of DKK1.…”

Section: Agonists Of Notch and Wnt Pathways In The Secretomementioning

confidence: 99%

“…Having demonstrated the effects of DKK3 and Jagged1 secreted from dysfunctional endothelial cells exerting paracrine effects on renal fibroblasts, it was only plausible to expect their autocrine effects. In experiments on DKK3 application to cultured RMVEC we found that DKK3 significantly increased the amount of RMVEC undergoing endothelial-mesenchymal transition ( Lipphardt et al, 2018a ). We also showed that RMVEC cultured on matrigel exhibited reduced total vessel length, percentage area occupied by capillary-like structures, and limited number of bifurcations after treatment with DKK3 ( Lipphardt et al, 2018a ).…”

Section: Autocrine Effects Of Endothelial Secretomementioning

confidence: 99%

“…In experiments on DKK3 application to cultured RMVEC we found that DKK3 significantly increased the amount of RMVEC undergoing endothelial-mesenchymal transition ( Lipphardt et al, 2018a ). We also showed that RMVEC cultured on matrigel exhibited reduced total vessel length, percentage area occupied by capillary-like structures, and limited number of bifurcations after treatment with DKK3 ( Lipphardt et al, 2018a ). As mentioned earlier, Jagged1 is also capable of inducing endothelial-mesenchymal transition and impairing angiogenesis.…”

Section: Autocrine Effects Of Endothelial Secretomementioning

confidence: 99%

See 1 more Smart Citation

Fibrogenic Secretome of Sirtuin 1-Deficient Endothelial Cells: Wnt, Notch and Glycocalyx Rheostat

Lipphardt

¹

,

Dihazi

²

,

Müller

³

et al. 2018

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Sirtuins (SIRT) are ubiquitous histone and protein deacetylases and a member of this family, SIRT1, is the best-studied one. Its functions in endothelial cells encompass branching angiogenesis, activation of endothelial nitric oxide synthase, regulation of proapoptotic and proinflammatory pathways, among others. Defective SIRT1 activity has been described in various cardiovascular, renal diseases and in aging-associated conditions. Therefore, understanding of SIRT1-deficient, endothelial dysfunctional phenotype has much to offer clinically. Here, we summarize recent studies by several investigative teams of the characteristics of models of global endothelial SIRT1 deficiency, the causes of facilitative development of fibrosis in these conditions, dissect the protein composition of the aberrant secretome of SIRT1-deficient endothelial cells and present several components of this aberrant secretome that are involved in fibrogenesis via activation of fibroblasts to myofibroblasts. These include ligands of Wnt and Notch pathways, as well as proteolytic fragments of glycocalyx core protein, syndecan-4. The latter finding is crucial for understanding the degradation of glycocalyx that accompanies SIRT1 deficiency. This spectrum of abnormalities associated with SIRT1 deficiency in endothelial cells is essential for understanding the origins and features of endothelial dysfunction in a host of cardiovascular and renal diseases.

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Dickkopf-3 in aberrant endothelial secretome triggers renal fibroblast activation and endothelial–mesenchymal transition

Cited by 50 publications

References 45 publications

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

Fibrogenic Secretome of Sirtuin 1-Deficient Endothelial Cells: Wnt, Notch and Glycocalyx Rheostat

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