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Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

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Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress. / Delitsikou, Vasiliki; Jarad, George; Rajaram, Renuga Devi; Ino, Frédérique; Rutkowski, Joseph M.; Chen, Ci Di; Santos, Celio X.C.; Scherer, Philipp E.; Abraham, Carmela R.; Shah, Ajay M.; Feraille, Eric; Miner, Jeffrey H.; de Seigneux, Sophie.

In: Faseb Journal, Vol. 34, No. 2, 01.02.2020, p. 2087-2104.

Research output: Contribution to journalArticle

Harvard

Delitsikou, V, Jarad, G, Rajaram, RD, Ino, F, Rutkowski, JM, Chen, CD, Santos, CXC, Scherer, PE, Abraham, CR, Shah, AM, Feraille, E, Miner, JH & de Seigneux, S 2020, 'Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress', Faseb Journal, vol. 34, no. 2, pp. 2087-2104. https://doi.org/10.1096/fj.201900893R

APA

Delitsikou, V., Jarad, G., Rajaram, R. D., Ino, F., Rutkowski, J. M., Chen, C. D., ... de Seigneux, S. (2020). Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress. Faseb Journal, 34(2), 2087-2104. https://doi.org/10.1096/fj.201900893R

Vancouver

Delitsikou V, Jarad G, Rajaram RD, Ino F, Rutkowski JM, Chen CD et al. Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress. Faseb Journal. 2020 Feb 1;34(2):2087-2104. https://doi.org/10.1096/fj.201900893R

Author

Delitsikou, Vasiliki ; Jarad, George ; Rajaram, Renuga Devi ; Ino, Frédérique ; Rutkowski, Joseph M. ; Chen, Ci Di ; Santos, Celio X.C. ; Scherer, Philipp E. ; Abraham, Carmela R. ; Shah, Ajay M. ; Feraille, Eric ; Miner, Jeffrey H. ; de Seigneux, Sophie. / Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress. In: Faseb Journal. 2020 ; Vol. 34, No. 2. pp. 2087-2104.

Bibtex Download

@article{73debf768dca4920af1150918ce299c7,
title = "Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress",
abstract = "Proteinuria is associated with renal function decline and cardiovascular mortality. This association may be attributed in part to alterations of Klotho expression induced by albuminuria, yet the underlying mechanisms are unclear. The presence of albumin decreased Klotho expression in the POD-ATTAC mouse model of proteinuric kidney disease as well as in kidney epithelial cell lines. This downregulation was related to both decreased Klotho transcription and diminished protein half-life, whereas cleavage by ADAM proteases was not modified. The regulation was albumin specific since it was neither observed in the analbuminemic Col4α3−/− Alport mice nor induced by exposure of kidney epithelial cells to purified immunoglobulins. Albumin induced features of ER stress in renal tubular cells with ATF3/ATF4 activation. ATF3 and ATF4 induction downregulated Klotho through altered transcription mediated by their binding on the Klotho promoter. Inhibiting ER stress with 4-PBA decreased the effect of albumin on Klotho protein levels without altering mRNA levels, thus mainly abrogating the increased protein degradation. Taken together, albuminuria decreases Klotho expression through increased protein degradation and decreased transcription mediated by ER stress induction. This implies that modulating ER stress may improve proteinuria-induced alterations of Klotho expression, and hence renal and extrarenal complications associated with Klotho loss.",
keywords = "albuminuria, ATF3, CKD, ER stress, Klotho",
author = "Vasiliki Delitsikou and George Jarad and Rajaram, {Renuga Devi} and Fr{\'e}d{\'e}rique Ino and Rutkowski, {Joseph M.} and Chen, {Ci Di} and Santos, {Celio X.C.} and Scherer, {Philipp E.} and Abraham, {Carmela R.} and Shah, {Ajay M.} and Eric Feraille and Miner, {Jeffrey H.} and {de Seigneux}, Sophie",
year = "2020",
month = "2",
day = "1",
doi = "10.1096/fj.201900893R",
language = "English",
volume = "34",
pages = "2087--2104",
journal = "Faseb Journal",
issn = "0892-6638",
publisher = "Federation of American Societies for Experimental Biology",
number = "2",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

AU - Delitsikou, Vasiliki

AU - Jarad, George

AU - Rajaram, Renuga Devi

AU - Ino, Frédérique

AU - Rutkowski, Joseph M.

AU - Chen, Ci Di

AU - Santos, Celio X.C.

AU - Scherer, Philipp E.

AU - Abraham, Carmela R.

AU - Shah, Ajay M.

AU - Feraille, Eric

AU - Miner, Jeffrey H.

AU - de Seigneux, Sophie

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Proteinuria is associated with renal function decline and cardiovascular mortality. This association may be attributed in part to alterations of Klotho expression induced by albuminuria, yet the underlying mechanisms are unclear. The presence of albumin decreased Klotho expression in the POD-ATTAC mouse model of proteinuric kidney disease as well as in kidney epithelial cell lines. This downregulation was related to both decreased Klotho transcription and diminished protein half-life, whereas cleavage by ADAM proteases was not modified. The regulation was albumin specific since it was neither observed in the analbuminemic Col4α3−/− Alport mice nor induced by exposure of kidney epithelial cells to purified immunoglobulins. Albumin induced features of ER stress in renal tubular cells with ATF3/ATF4 activation. ATF3 and ATF4 induction downregulated Klotho through altered transcription mediated by their binding on the Klotho promoter. Inhibiting ER stress with 4-PBA decreased the effect of albumin on Klotho protein levels without altering mRNA levels, thus mainly abrogating the increased protein degradation. Taken together, albuminuria decreases Klotho expression through increased protein degradation and decreased transcription mediated by ER stress induction. This implies that modulating ER stress may improve proteinuria-induced alterations of Klotho expression, and hence renal and extrarenal complications associated with Klotho loss.

AB - Proteinuria is associated with renal function decline and cardiovascular mortality. This association may be attributed in part to alterations of Klotho expression induced by albuminuria, yet the underlying mechanisms are unclear. The presence of albumin decreased Klotho expression in the POD-ATTAC mouse model of proteinuric kidney disease as well as in kidney epithelial cell lines. This downregulation was related to both decreased Klotho transcription and diminished protein half-life, whereas cleavage by ADAM proteases was not modified. The regulation was albumin specific since it was neither observed in the analbuminemic Col4α3−/− Alport mice nor induced by exposure of kidney epithelial cells to purified immunoglobulins. Albumin induced features of ER stress in renal tubular cells with ATF3/ATF4 activation. ATF3 and ATF4 induction downregulated Klotho through altered transcription mediated by their binding on the Klotho promoter. Inhibiting ER stress with 4-PBA decreased the effect of albumin on Klotho protein levels without altering mRNA levels, thus mainly abrogating the increased protein degradation. Taken together, albuminuria decreases Klotho expression through increased protein degradation and decreased transcription mediated by ER stress induction. This implies that modulating ER stress may improve proteinuria-induced alterations of Klotho expression, and hence renal and extrarenal complications associated with Klotho loss.

KW - albuminuria

KW - ATF3

KW - CKD

KW - ER stress

KW - Klotho

UR - http://www.scopus.com/inward/record.url?scp=85078677220&partnerID=8YFLogxK

U2 - 10.1096/fj.201900893R

DO - 10.1096/fj.201900893R

M3 - Article

C2 - 31907991

AN - SCOPUS:85078677220

VL - 34

SP - 2087

EP - 2104

JO - Faseb Journal

JF - Faseb Journal

SN - 0892-6638

IS - 2

ER -

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