Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin

Navid M. Farsijani, Qingdu Liu, Hanako Kobayashi, Olena Davidoff, Feng Sha, Joachim Fandrey, T. Alp Ikizler, Paul M O'Connor, Volker H. Haase

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The adult kidney plays a central role in erythropoiesis and is the main source of erythropoietin (EPO), an oxygen-sensitive glycoprotein that is essential for red blood cell production. Decreases of renal pO2 promote hypoxia-inducible factor 2-mediated (HIF-2-mediated) induction of EPO in peritubular interstitial fibroblast-like cells, which serve as the cellular site of EPO synthesis in the kidney. It is not clear whether HIF signaling in other renal cell types also contributes to the regulation of EPO production. Here, we used a genetic approach in mice to investigate the role of renal epithelial HIF in erythropoiesis. Specifically, we found that HIF activation in the proximal nephron via induced inactivation of the von Hippel-Lindau tumor suppressor, which targets the HIF-α subunit for proteasomal degradation, led to rapid development of hypoproliferative anemia that was associated with a reduction in the number of EPO-producing renal interstitial cells. Moreover, suppression of renal EPO production was associated with increased glucose uptake, enhanced glycolysis, reduced mitochondrial mass, diminished O2 consumption, and elevated renal tissue pO2. Our genetic analysis suggests that tubulointerstitial cellular crosstalk modulates renal EPO production under conditions of epithelial HIF activation in the kidney.

Original languageEnglish (US)
Pages (from-to)1425-1437
Number of pages13
JournalJournal of Clinical Investigation
Volume126
Issue number4
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Medicine(all)

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    Farsijani, N. M., Liu, Q., Kobayashi, H., Davidoff, O., Sha, F., Fandrey, J., Ikizler, T. A., O'Connor, P. M., & Haase, V. H. (2016). Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. Journal of Clinical Investigation, 126(4), 1425-1437. https://doi.org/10.1172/JCI74997