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

Abstract

<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 genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of <i>Xbp1</i> and <i>Sec63</i> worsens PKD in this model. We explored the renal effects of postnatal inactivation of <i>Sec63</i> alone or with concomitant inactivation of <i>Xbp1</i> or <i>Ire1α</i>, specifically in the collecting ducts of neonatal mice. The later onset of inactivation of <i>Sec63</i> restricted to the collecting duct does not result in overt activation of the Ire1<i>α</i>-Xbp1 pathway or cause polycystin-1-dependent PKD. Inactivating <i>Sec63</i> along with either <i>Xbp1</i> or <i>Ire1α</i> in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s <i>in vivo</i> completely rescues the chronic kidney injury observed after inactivation of <i>Sec63</i> with either <i>Xbp1</i> or <i>Ire1α</i>. In the absence of <i>Sec63</i>, 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 <i>Sec63-Xbp1</i> 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.