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


ABSTRACT:

Background

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 Ire1?-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.

Methods

We explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1?, specifically in the collecting ducts of neonatal mice.

Results

The later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1?-Xbp1 pathway or cause polycystin-1-dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1? 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 Ire1?.

Conclusions

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.

SUBMITTER: Ishikawa Y 

PROVIDER: S-EPMC6405156 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of <i>Sec63</i> in Collecting Ducts.

Ishikawa Yasunobu Y   Fedeles Sorin S   Marlier Arnaud A   Zhang Chao C   Gallagher Anna-Rachel AR   Lee Ann-Hwee AH   Somlo Stefan S  

Journal of the American Society of Nephrology : JASN 20190211 3


<h4>Background</h4><i>SEC63</i> encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of <i>Sec63</i> in all distal nephron segments in embryonic mouse kidney results in polycystin-1-mediated polycystic kidney disease (PKD). It also activates the Ire1<i>α</i>-Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific  ...[more]

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