title: Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes.
abstract: Podocytes are terminally differentiated epithelial cells that reside along the glomerular filtration barrier. Evidence suggests that after podocyte injury, endoplasmic reticulum stress response is activated, but the molecular mechanisms involved are incompletely defined. In a mouse model, we confirmed that podocyte injury induces endoplasmic reticulum stress response and upregulated unfolded protein response pathways, which have been shown to mitigate damage by preventing the accumulation of misfolded proteins in the endoplasmic reticulum. Furthermore, simultaneous podocyte-specific genetic inactivation of X-box binding protein-1 (Xbp1), a transcription factor activated during endoplasmic reticulum stress and critically involved in the untranslated protein response, and Sec63, a heat shock protein-40 chaperone required for protein folding in the endoplasmic reticulum, resulted in progressive albuminuria, foot process effacement, and histology consistent with ESRD. Finally, loss of both Sec63 and Xbp1 induced apoptosis in podocytes, which associated with activation of the JNK pathway. Collectively, our results indicate that an intact Xbp1 pathway operating to mitigate stress in the endoplasmic reticulum is essential for the maintenance of a normal glomerular filtration barrier.
authors: Department of Pediatrics.
authors: Hossam
authors: H
authors: Hassan
authors: Internal Medicine, and.
authors: Xuefei
authors: X
authors: Tian
authors: Internal Medicine, and.
authors: Kazunori
authors: K
authors: Inoue
authors: Internal Medicine, and.
authors: Nathan
authors: N
authors: Chai
authors: Internal Medicine, and.
authors: Chang
authors: C
authors: Liu
authors: Internal Medicine, and.
authors: Keita
authors: K
authors: Soda
authors: Pathology, Yale University School of Medicine, New Haven, Connecticut, and.
authors: Gilbert
authors: G
authors: Moeckel
authors: Department of Pediatrics.
authors: Alda
authors: A
authors: Tufro
authors: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors: Ann-Hwee
authors: AH
authors: Lee
authors: Internal Medicine, and.
authors: Stefan
authors: S
authors: Somlo
authors: Internal Medicine, and.
authors: Sorin
authors: S
authors: Fedeles
authors: Internal Medicine, and shuta.ishibe@yale.edu.
authors: Shuta
authors: S
authors: Ishibe
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D051379:Mice; D050199:Podocytes / Q000502:physiology*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse
keywords: glomerular epithelial cells; glomerulosclerosis; proteinuria