Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin
Hanako Kobayashi, … , Kenneth W. Gross, Volker H. Haase
Hanako Kobayashi, … , Kenneth W. Gross, Volker H. Haase
Published April 18, 2016
Citation Information: J Clin Invest. 2016;126(5):1926-1938. https://doi.org/10.1172/JCI83551.
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Research Article Nephrology

Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin

Abstract

Renal peritubular interstitial fibroblast-like cells are critical for adult erythropoiesis, as they are the main source of erythropoietin (EPO). Hypoxia-inducible factor 2 (HIF-2) controls EPO synthesis in the kidney and liver and is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3, which function as cellular oxygen sensors. Renal interstitial cells with EPO-producing capacity are poorly characterized, and the role of the PHD/HIF-2 axis in renal EPO-producing cell (REPC) plasticity is unclear. Here we targeted the PHD/HIF-2/EPO axis in FOXD1 stroma-derived renal interstitial cells and examined the role of individual PHDs in REPC pool size regulation and renal EPO output. Renal interstitial cells with EPO-producing capacity were entirely derived from FOXD1-expressing stroma, and Phd2 inactivation alone induced renal Epo in a limited number of renal interstitial cells. EPO induction was submaximal, as hypoxia or pharmacologic PHD inhibition further increased the REPC fraction among Phd2–/– renal interstitial cells. Moreover, Phd1 and Phd3 were differentially expressed in renal interstitium, and heterozygous deficiency for Phd1 and Phd3 increased REPC numbers in Phd2–/– mice. We propose that FOXD1 lineage renal interstitial cells consist of distinct subpopulations that differ in their responsiveness to Phd2 inactivation and thus regulation of HIF-2 activity and EPO production under hypoxia or conditions of pharmacologic or genetic PHD inactivation.

Authors

Hanako Kobayashi, Qingdu Liu, Thomas C. Binns, Andres A. Urrutia, Olena Davidoff, Pinelopi P. Kapitsinou, Andrew S. Pfaff, Hannes Olauson, Annika Wernerson, Agnes B. Fogo, Guo-Hua Fong, Kenneth W. Gross, Volker H. Haase

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Figure 7

REPC topography in anemic mice differs from that in Foxd1-Phd2–/– mice.

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REPC topography in anemic mice differs from that in Foxd1-Phd2–/– mice. ...
Shown are representative annotated images illustrating the distribution of REPCs in anemic control and in Foxd1-Phd2–/– mice. Epo ISH studies were performed using formalin-fixed, paraffin-embedded kidney tissue sections. (A–D) Epo transcripts were detected by red signals in original images. To facilitate visualization and to provide an overview of Epo transcript distribution at low magnification, Epo+ cells were annotated with red circles. (A) Kidney section from control mouse at baseline. (B) Kidney section from control mouse with Hct of 26%. (C) Kidney section from control mouse with Hct of 15%. (D) Representative low-magnification image of kidney from a Foxd1-Phd2–/– mutant. (E) Representative high-magnification image of Epo ISH from control mouse with Hct of 15% to illustrate how Epo+ cells were annotated. rbc are denoted by white arrows. White dashed lines indicate borders between cortex, outer stripe (OS) and inner stripe (IS) of outer medulla, and inner medulla (IM). Scale bars: 1 mm (A–D), 50 μm (E). (F) Shown is the relative distribution of Epo-expressing cells in the outer (i), mid– (ii), and inner (iii) renal cortex from control mice at baseline (n = 4) and after phlebotomy (n = 5), Foxd1-mT/mG-Phd2–/– (Phd2–/–) mutants at baseline (n = 5) and after phlebotomy (n = 5), Foxd1-mT/mG-Phd1+/–-Phd2–/–-Phd3+/– (Phd1+/– Phd2–/– Phd3+/–) mutants (n = 3), and Foxd1-mT/mG-Phd2–/– mice treated with GSK1002083A (Phd2–/– + PHI; n = 4). Data are represented as mean ± SEM. OM, outer medulla.