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J Am Soc Nephrol. 2016 Apr;27(4):1055-65. doi: 10.1681/ASN.2015020191. Epub 2015 Aug 24.

Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes.

Author information

1
Department of Pediatrics.
2
Internal Medicine, and.
3
Pathology, Yale University School of Medicine, New Haven, Connecticut, and.
4
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
5
Internal Medicine, and shuta.ishibe@yale.edu.

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.

KEYWORDS:

glomerular epithelial cells; glomerulosclerosis; proteinuria

PMID:
26303067
PMCID:
PMC4814187
DOI:
10.1681/ASN.2015020191
[Indexed for MEDLINE]
Free PMC Article

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