TY - JOUR
T1 - Inhibition of reticulon-1a-mediated endoplasmic reticulum stress in early aki attenuates renal fibrosis development
AU - Fan, Ying
AU - Xiao, Wenzhen
AU - Lee, Kyung
AU - Salem, Fadi
AU - Wen, Jiejun
AU - He, Li
AU - Zhang, Jing
AU - Fei, Yang
AU - Cheng, Dongsheng
AU - Bao, Hongda
AU - Liu, Yumei
AU - Lin, Fujun
AU - Jiang, Gengru
AU - Guo, Zhiyong
AU - Wang, Niansong
AU - He, John Cijiang
N1 - Publisher Copyright:
© 2017 by the American Society of Nephrology.
PY - 2017/7
Y1 - 2017/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85021756452&partnerID=8YFLogxK
U2 - 10.1681/ASN.2016091001
DO - 10.1681/ASN.2016091001
M3 - Article
C2 - 28137829
AN - SCOPUS:85021756452
SN - 1046-6673
VL - 28
SP - 2007
EP - 2021
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 7
ER -