Periostin, a Matricellular Protein, Plays a Role in the Induction of Chemokines in Pulmonary Fibrosis

Kavvadas

Kormann

et al. 2016

JASN

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.

Section: Discussionmentioning

confidence: 99%

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

Kavvadas

Kormann

et al. 2016

JASN

“…In animal and in vitro studies, Postn was shown to mediate pulmonary fibrosis by promoting the production of pro-inflammatory cytokines and inducing secretion of collagen by lung fibroblasts (38)(39)(40). In recent clinical studies, high serum Postn levels could predict a shortened survival and worsened outcome with increased fibrosis in patients with IPF (41).…”

Section: Periostinmentioning

confidence: 99%

Matricellular Proteins and Organ Fibrosis

Chatziantoniou

2017

Curr Pathobiol Rep

“…Studies in a model of cardiac fibrosis indicated that periostin may act as a downstream mediator of Ang II signaling through complex interactions that involve p38/ CREB and erk/TGF-β pathways [14]. Additionally, lung fibroblasts from periostin-/-animals had an impaired response to TNF-α, and they failed to produce chemokines and pro-inflammatory cytokines, indicating that periostin could mediate both the inflammatory and the fibrotic process [15].…”

Section: Periostinmentioning

confidence: 99%

New Targets for End-Stage Chronic Kidney Disease Therapy

The Journal of Critical Care Medicine

Kavvadas

Chatziantoniou

2015

Severe forms of chronic kidney disease can lead to a critical, end-stage condition, requiring renal replacement therapy, which may involve a form of dialysis or renal transplantation. Identification and characterization of novel markers and/or targets of therapy that could be applied in these critically ill patients remains the focus of the current research in the field of critical care medicine and has been the objective of our studies for some years past. To this end, we used models of renal vascular disease, Ang II, L-NAME or mice overexpressing renin, treated with AT1 antagonists at different stages of progression, to create cohorts of animals during progression, reversal or escape from therapy. Transcriptomic analysis and comparisons were performed and genes were selected according to the following criteria: a) not previously described in the kidney, b) highly upregulated during progression and returning to the normal levels during reversal, and c) producing proteins that are either circulating or membrane receptors. The involvement of the selected genes in the mechanisms of renal disease was confirmed in additional models of renal disease, initiated in other compartments of the kidney such as glomeruli (administration of nephrotoxic serum) or the tubular interstitium (unilateral ureteral obstruction). The potential of the therapy was tested using mice lacking the expression of these genes and by in vivo administration of antisense oligonucleotides which blocked the transcription of the targeted genes. This strategy allowed the identification of periostin, an extracellular matrix protein normally involved in bone and tooth development, in addition to the discoidin domain receptor1 (DDR1) as potential targets of therapy against renal inflammation and fibrosis.