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

Abstract

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 NFκB 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-β3 and phosphorylation of focal adhesion kinase and AKT, known mediators of integrin-β3 signaling that affect cell motility and survival, observed during GN in wild-type animals. In vitro, recombinant periostin increased the expression of integrin-β3 and the concomitant phosphorylation of focal adhesion kinase and AKT in podocytes. Notably, periostin and integrin-β3 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-β3 signaling. Targeting periostin may be a novel therapeutic strategy for treating CKD.

• Authors: Niki Prakoura, Panagiotis Kavvadas, Raphaёl Kormann, Jean-Claude Dussaule, Christos E Chadjichristos, Christos Chatziantoniou
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 28 Issue 5 Pg. 1475-1490 (May 2017) ISSN: 1533-3450 [Electronic] United States
• PMID: 27920156 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 by the American Society of Nephrology.

Chemical References

• Cell Adhesion Molecules
• Integrin beta3
• NF-kappa B
• Postn protein, mouse

Topics

• Animals
• Cell Adhesion Molecules (physiology)
• Female
• Glomerulonephritis (complications)
• Integrin beta3 (physiology)
• Kidney Diseases (etiology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (physiology)
• Signal Transduction