Inhibition of reticulon-1a-mediated endoplasmic reticulum stress in early aki attenuates renal fibrosis development

Ying Fan, Wenzhen Xiao, Kyung Lee, Fadi Salem, Jiejun Wen, Li He, Jing Zhang, Yang Fei, Dongsheng Cheng, Hongda Bao, Yumei Liu, Fujun Lin, Gengru Jiang, Zhiyong Guo, Niansong Wang, John Cijiang He

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Several animal studies have shown an important role for endoplasmic reticulum(ER) stress in AKI, whereas human studies are lacking.We recently reported that Reticulon-1A (RTN1A) is a key mediator of ER stress and kidney cell injury. Here, we investigated whethermodulation of RTN1A expression during AKI contributes to the progression toCKD. In a retrospective study of 51 patientswithAKI, increased expression ofRTN1Aand other ER stress markers were associated with the severity of kidney injury and with progression to CKD. In an inducible tubular cell-specific RTN1A-knockdown mouse model subjected to folic acid nephropathy (FAN) or aristolochic acid nephropathy, reduction of RTN1A expression during the initial stage of AKI attenuated ER stress and kidney cell injury in early stages and renal fibrosis development in later stages. Treatment of wild-type mice with tauroursodeoxycholic acid, an inhibitor of ER stress, after the induction of kidney injury with FA facilitated renoprotection similar to that observed in RTN1A-knockdownmice. Conversely, in transgenicmice with inducible tubular cell-specific overexpression of RTN1A subjected to FAN, induction of RTN1A overexpression aggravated ER stress and renal injury at the early stage and renal fibrosis at the late stage ofFAN.Together,ourhuman andmouse data suggest that the RTN1A-mediated ER stress responsemay be an important determinant in the severity ofAKI and maladaptive repair that may promote progression to CKD.

Original languageEnglish
Pages (from-to)2007-2021
Number of pages15
JournalJournal of the American Society of Nephrology
Volume28
Issue number7
DOIs
StatePublished - Jul 2017
Externally publishedYes

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