title: Altered unfolded protein response is implicated in the age-related exacerbation of proteinuria-induced proximal tubular cell damage.
abstract: Aging is a dominant risk factor for end-stage renal disease. We analyzed the mechanism involved in age-related exacerbation of proteinuria-induced proximal tubular cell (PTC) damage by focusing on endoplasmic reticulum-related unfolded protein response (UPR). After equal-degree induction of proteinuria in 24-month-old (aged) and 3-month-old (young) mice by intraperitoneal free fatty acid-bound albumin overload, tubulointerstitial lesions were more severe in aged than in young mice. In aged PTCs, proteinuria-induced cell-adaptive UPR resulting from induction of the molecular chaperone BiP was significantly suppressed, whereas proapoptotic UPR with CHOP overexpression was enhanced. Treatment with the exogenous molecular chaperone tauroursodeoxycholic acid (TUDCA) ameliorated proteinuria-induced tubulointerstitial lesions and PTC apoptosis in aged mice. Among the three UPR branches, alterations in the inositol-requiring 1α (IRE1α) pathway, but not the activating transcription factor 6 or PERK pathway, were associated with impaired BiP induction in aged kidneys. Moreover, siRNA-mediated suppression of BiP and IRE1α exacerbated free fatty acid-bound albumin-induced apoptosis in cultured PTCs, whereas siRNA-mediated CHOP suppression ameliorated apoptosis. Finally, proteinuria-induced BiP induction in PTCs was diminished in kidney specimens from elderly patients. These results indicate that maladaptive UPRs are involved in proteinuria-induced tubulointerstitial lesions exacerbation in aged kidneys, and that supplementation of chaperones may be used to treat elderly patients with persistent proteinuria. These results should improve understanding of cell vulnerability in aged kidneys.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takeda
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Yoshikata
authors.initials: Y
authors.lastname: Morita
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.forename: Hisazumi
authors.initials: H
authors.lastname: Araki
authors.forename: Keiji
authors.initials: K
authors.lastname: Isshiki
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Araki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Uzu
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000473:pathology*; D000418:Albumins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011507:Proteinuria / Q000150:complications* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000418:Albumins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010168:Palmitates; D051742:Transcription Factor CHOP; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases