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

17 Citations (Scopus)

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

Fingerprint

Erythropoiesis
Erythropoietin
Epithelium
Kidney
Nephrons
Glycolysis
Anemia
Glycoproteins
Fibroblasts
Erythrocytes
Oxygen
Glucose

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Farsijani, N. M., Liu, Q., Kobayashi, H., Davidoff, O., Sha, F., Fandrey, J., ... 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

Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. / Farsijani, Navid M.; Liu, Qingdu; Kobayashi, Hanako; Davidoff, Olena; Sha, Feng; Fandrey, Joachim; Ikizler, T. Alp; O'Connor, Paul M; Haase, Volker H.

In: Journal of Clinical Investigation, Vol. 126, No. 4, 01.04.2016, p. 1425-1437.

Research output: Contribution to journalArticle

Farsijani, NM, Liu, Q, Kobayashi, H, Davidoff, O, Sha, F, Fandrey, J, Ikizler, TA, O'Connor, PM & Haase, VH 2016, 'Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin', Journal of Clinical Investigation, vol. 126, no. 4, pp. 1425-1437. https://doi.org/10.1172/JCI74997
Farsijani NM, Liu Q, Kobayashi H, Davidoff O, Sha F, Fandrey J et al. Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. Journal of Clinical Investigation. 2016 Apr 1;126(4):1425-1437. https://doi.org/10.1172/JCI74997
Farsijani, Navid M. ; Liu, Qingdu ; Kobayashi, Hanako ; Davidoff, Olena ; Sha, Feng ; Fandrey, Joachim ; Ikizler, T. Alp ; O'Connor, Paul M ; Haase, Volker H. / Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 4. pp. 1425-1437.
@article{398d312d7cca426eb693619b93930952,
title = "Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin",
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.",
author = "Farsijani, {Navid M.} and Qingdu Liu and Hanako Kobayashi and Olena Davidoff and Feng Sha and Joachim Fandrey and Ikizler, {T. Alp} and O'Connor, {Paul M} and Haase, {Volker H.}",
year = "2016",
month = "4",
day = "1",
doi = "10.1172/JCI74997",
language = "English (US)",
volume = "126",
pages = "1425--1437",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

TY - JOUR

T1 - Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin

AU - Farsijani, Navid M.

AU - Liu, Qingdu

AU - Kobayashi, Hanako

AU - Davidoff, Olena

AU - Sha, Feng

AU - Fandrey, Joachim

AU - Ikizler, T. Alp

AU - O'Connor, Paul M

AU - Haase, Volker H.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84964612367&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964612367&partnerID=8YFLogxK

U2 - 10.1172/JCI74997

DO - 10.1172/JCI74997

M3 - Article

VL - 126

SP - 1425

EP - 1437

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -