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 5

Differential expression of PDGFRB in murine and human EPO-producing renal interstitial cells.

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Differential expression of PDGFRB in murine and human EPO-producing rena...
(A) Shown are representative images from ISH studies simultaneously detecting Epo (red signal), EGFP (green signal), and Pdgfrb (blue signal) transcripts in formalin-fixed, paraffin-embedded kidney tissue sections from Foxd1-Phd2–/– mutant mice. The red arrowhead depicts a representative Epo+Pdfgrb+ interstitial cell; the black arrowhead depicts a representative Epo–Pdgfrb+ cell. Bottom right panel: Quantification of Epo-expressing cells within Pdgfrb+ and Pdgfrb– cell populations expressed as percentage (n = 4). Scale bars: 50 μm (low-magnification panel), 10 μm (high-magnification panels). Graph bars represent mean ± SEM; 2-tailed Student’s t test; ***P < 0.001. (B) ISH for EPO (red signal) and PDGFRB (blue signal) in human renal tissue. Top panel: Low-magnification image of large tissue section from normal kidney. EPO-expressing cells were detected in areas highlighted by red boxes (total of 63 EPO+ cells; 12 EPO+ cells were negative for PDGFRB). Bottom panels: Representative images of cells expressing both PDGFRB and EPO (red arrowheads) and interstitial EPO-expressing cells with nondetectable PDGFRB transcripts (white arrowhead). Scale bars: 1 mm (top panel), 10 μm (bottom panels).