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

Background: encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of 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 and worsens PKD in this model.

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

Results: The later onset of inactivation of restricted to the collecting duct does not result in overt activation of the Ire1-Xbp1 pathway or cause polycystin-1-dependent PKD. Inactivating along with either or in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s completely rescues the chronic kidney injury observed after inactivation of with either or .

Conclusions: In the absence of , 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 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.