Invariant Natural Killer T Cells and TGF-β Attenuate Anti-GBM Glomerulonephritis

Laurent, Michel; Keller, Alexandre C.; Michel, Marie‐Laure; Vandermeersch, Sophie; Rafat, Cédric; Letavernier, Emmanuel; Tillet, Yves; Rondeau, Éric; Leite‐de‐Moraes, Maria

doi:10.1681/asn.2008040433

Cited by 54 publications

(54 citation statements)

References 54 publications

(68 reference statements)

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“…8 Glomerulonephritis was induced in male C57BL/6 wild type (WT) or CalpTG mice as described previously. 23 Renal injury was evaluated on days 7 and 14. Specimens of kidney were cut for histochemistry and immunohistochemistry studies.…”

Section: Methodsmentioning

confidence: 99%

Calpains Contribute to Vascular Repair in Rapidly Progressive Form of Glomerulonephritis: Potential Role of Their Externalization

Letavernier

Zafrani

Nassar

et al. 2012

ATVB

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Objective-Calpains, calcium-activated proteases, mediate the angiogenic signals of vascular endothelial growth factor.However, their involvement in vascular repair has not been investigated and the underlying mechanisms remain to be fully elucidated. Methods and Results-A rapidly progressive form of glomerulonephritis in wild type and transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor, was studied. Calpastatin transgene expression prevented the repair of peritubular capillaries and the recovery of renal function, limiting mouse survival. In vitro analysis detected a significant reduction of both intracellular and extracellular calpain activities in transgene expressing cells, whereas Western blotting revealed that proangiogenic factors vascular endothelial growth factor and norepinephrine increased calpain exteriorization. In vitro, extracellular calpains increased endothelial cell proliferation, migration and capillary tube formation. In vivo, delivery of nonpermeable extracellular calpastatin was sufficient to blunt angiogenesis and vascular repair. Endothelial cell response to extracellular calpains was associated with fibronectin cleavage, generating fibronectin fragments with proangiogenic capacity. In vivo, fibronectin cleavage was limited in the kidney of calpastatin transgenic mice with nephritis. Conclusion-This

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Section: Methodsmentioning

confidence: 99%

Calpains Contribute to Vascular Repair in Rapidly Progressive Form of Glomerulonephritis: Potential Role of Their Externalization

Letavernier

Zafrani

Nassar

et al. 2012

ATVB

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“…15 For the model of NTS-induced GN, decomplemented NTS was prepared as previously described. 37,38 Female wild-type and KO littermate mice of the C57BL/6 background (8-10 weeks old) received intravenous injections of 15 ml NTS per g body wt over two consecutive days (days 0 and 1) to induce crescentic GN. Control mice were injected with PBS.…”

Section: Animal Modelsmentioning

confidence: 99%

NFκB-Induced Periostin Activates Integrin-β3 Signaling to Promote Renal Injury in GN

Prakoura

Kavvadas

Kormann

et al. 2016

JASN

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De novo expression in the kidney of periostin, a protein involved in odontogenesis and osteogenesis, has been suggested as a biomarker of renal disease. In this study, we investigated the mechanism(s) of induction and the role of periostin in renal disease. Using a combination of bioinformatics, reporter assay, and chromatin immunoprecipitation analyses, we found that NFkB and other proinflammatory transcription factors induce periostin expression in vitro and that binding of these factors on the periostin promoter is enriched in glomeruli during experimental GN. Mice lacking expression of periostin displayed preserved renal function and structure during GN. Furthermore, delayed administration of periostin antisense oligonucleotides in wild-type animals with GN reversed already established proteinuria, diminished tissue inflammation, and improved renal structure. Lack of periostin expression also blunted the de novo renal expression of integrin-b3 and phosphorylation of focal adhesion kinase and AKT, known mediators of integrin-b3 signaling that affect cell motility and survival, observed during GN in wild-type animals. In vitro, recombinant periostin increased the expression of integrin-b3 and the concomitant phosphorylation of focal adhesion kinase and AKT in podocytes. Notably, periostin and integrin-b3 were highly colocalized in biopsy specimens from patients with inflammatory GN. These results demonstrate that interplay between periostin and renal inflammation orchestrates inflammatory and fibrotic responses, driving podocyte damage through downstream activation of integrin-b3 signaling. Targeting periostin may be a novel therapeutic strategy for treating CKD.

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“…Decomplemented NTS was prepared as previously described. 27 Female mice (aged 3 months) received intravenous injections of a total 30 ml of NTS/g body weight over 3 consecutive days (days 0, 1, and 2) to induce crescentic GN. Control mice were injected with PBS.…”

Section: Animalsmentioning

confidence: 99%

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

Machhour

Keuylian

Kavvadas

et al. 2015

Journal of the American Society of Nephrology

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Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN.

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Invariant Natural Killer T Cells and TGF-β Attenuate Anti-GBM Glomerulonephritis

Cited by 54 publications

References 54 publications

Calpains Contribute to Vascular Repair in Rapidly Progressive Form of Glomerulonephritis: Potential Role of Their Externalization

Calpains Contribute to Vascular Repair in Rapidly Progressive Form of Glomerulonephritis: Potential Role of Their Externalization

NFκB-Induced Periostin Activates Integrin-β3 Signaling to Promote Renal Injury in GN

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

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