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

Research output: Contribution to journalArticle


  • Vasiliki Delitsikou
  • George Jarad
  • Renuga Devi Rajaram
  • Frédérique Ino
  • Joseph M. Rutkowski
  • Ci Di Chen
  • Celio X.C. Santos
  • Philipp E. Scherer
  • Carmela R. Abraham
  • Ajay M. Shah
  • Eric Feraille
  • Jeffrey H. Miner
  • Sophie de Seigneux

External Institution(s)

  • University of Geneva
  • Washington University St. Louis
  • Boston University
  • British Heart Foundation
  • University of Texas Southwestern Medical Center


Original languageEnglish (US)
Pages (from-to)2087-2104
Number of pages18
JournalFASEB Journal
Issue number2
StatusPublished - Feb 1 2020


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.

    Research areas

  • ATF3, CKD, ER stress, Klotho, albuminuria

Citation formats


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


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