Deletion of inositol-requiring enzyme-1? in podocytes disrupts glomerular capillary integrity and autophagy.

ABSTRACT: Inositol-requiring enzyme-1? (IRE1?) is an endoplasmic reticulum (ER)-transmembrane endoribonuclease kinase that plays an essential function in extraembryonic tissues during normal development and is activated during ER stress. To address the functional role of IRE1? in glomerular podocytes, we produced podocyte-specific IRE1?-deletion mice. In male mice, deletion of IRE1? in podocytes resulted in albuminuria beginning at 5 mo of age and worsening with time. Electron microscopy revealed focal podocyte foot-process effacement in 9-mo-old male IRE1?-deletion mice, as well as microvillous transformation of podocyte plasma membranes. Compared with control, glomerular cross-sectional and capillary lumenal areas were greater in deletion mice, and there was relative podocyte depletion. Levels of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II expression and c-Jun N-terminal kinase-1 phosphorylation were decreased in IRE1?-deletion glomeruli, in keeping with reduced autophagy. Deletion of IRE1? exacerbated glomerular injury in anti-glomerular basement membrane nephritis. In cell culture, IRE1? dominant-negative mutants reduced the physiological (basal) accumulation of LC3B-II and the size of autophagic vacuoles but did not affect ER-associated degradation. Thus IRE1? is essential for maintaining podocyte and glomerular integrity as mice age and in glomerulonephritis. The mechanism is related, at least in part, to the maintenance of autophagy in podocytes.

SUBMITTER: Kaufman DR 

PROVIDER: S-EPMC5469607 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature