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J Am Soc Nephrol. 2019 Feb 11. pii: ASN.2018060614. doi: 10.1681/ASN.2018060614. [Epub ahead of print]

Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts.

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Departments of Internal Medicine and.
Departments of Internal Medicine and
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
Genetics, Yale University School of Medicine, New Haven, Connecticut; and.



SEC63 encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of Sec63 in all distal nephron segments in embryonic mouse kidney results in polycystin-1-mediated polycystic kidney disease (PKD). It also activates the Ire1α-Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of Xbp1 and Sec63 worsens PKD in this model.


We explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1α, specifically in the collecting ducts of neonatal mice.


The later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1α-Xbp1 pathway or cause polycystin-1-dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1α in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s in vivo completely rescues the chronic kidney injury observed after inactivation of Sec63 with either Xbp1 or Ire1α.


In the absence of Sec63, basal levels of Xbp1s activity in collecting ducts is both necessary and sufficient to maintain proteostasis (protein homeostasis) and protect against inflammation, myofibroblast activation, and kidney functional decline. The Sec63-Xbp1 double knockout mouse offers a novel genetic model of chronic tubulointerstitial kidney injury, using collecting duct proteostasis defects as a platform for discovery of signals that may underlie CKD of disparate etiologies.


chronic kidney disease; endoplasmic reticulum; genetic renal disease; renal fibrosis; renal tubular epithelial cells

[Available on 2020-03-01]

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