Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response

Kidney Int. 2018 Sep;94(3):536-550. doi: 10.1016/j.kint.2018.03.011. Epub 2018 Jun 7.


Lipotoxicity plays an important role in the progression of chronic kidney damage via various mechanisms, such as endoplasmic reticulum stress. Several studies proposed renal lipotoxicity in glomerular and tubular cells but the effect of lipid on renal erythropoietin (EPO)-producing (REP) cells in the interstitium has not been elucidated. Since renal anemia is caused by derangement of EPO production in REP cells, we evaluated the effect of palmitate, a representative long-chain saturated fatty acid, on EPO production and the endoplasmic reticulum stress pathway. EPO production was suppressed by palmitate (palmitate-conjugated bovine serum albumin [BSA]) or a high palmitate diet, but not oleic acid-conjugated BSA or a high oleic acid diet, especially under cobalt-induced pseudo-hypoxia both in vitro and in vivo. Importantly, suppression of EPO production was not induced by a decrease in transcription factor HIF activity, while it was significantly associated with endoplasmic reticulum stress, particularly transcription factor ATF4 activation, which suppresses 3'-enhancer activity of the EPO gene. ATF4 knockdown by siRNA significantly attenuated the suppressive effect of palmitate on EPO production. Studies utilizing inherited super-anemic mice (ISAM) mated with EPO-Cre mice (ISAM-REC mice) for lineage-labeling of REP cells showed that ATF4 activation by palmitate suppressed EPO production in REP cells. Laser capture microdissection confirmed ATF4 activation in the interstitial area of ISAM-REC mice treated with palmitate-conjugated BSA. Thus, endoplasmic reticulum stress induced by palmitate suppressed EPO expression by REP cells in a manner independent of HIF activation. The link between endoplasmic reticulum stress, dyslipidemia, and hypoxia may contribute to development and progression of anemia in CKD.

Keywords: anemia; endoplasmic reticulum; erythropoietin; fibrosis; hypoxia; lipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Anemia / blood
  • Anemia / etiology
  • Anemia / pathology*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress
  • Erythropoietin / blood
  • Erythropoietin / genetics
  • Erythropoietin / metabolism*
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Humans
  • Kidney / metabolism*
  • Laser Capture Microdissection
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Palmitates / metabolism*
  • RNA, Small Interfering / metabolism
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / pathology
  • Unfolded Protein Response


  • ATF4 protein, human
  • Atf4 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • EPO protein, human
  • Epo protein, mouse
  • Palmitates
  • RNA, Small Interfering
  • Erythropoietin
  • Activating Transcription Factor 4
  • endothelial PAS domain-containing protein 1