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.
View: Text | PDF
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

×

Figure 8

Phd1 and Phd3 are differentially expressed in Phd2–/– renal interstitial cells.

Options: View larger image (or click on image) Download as PowerPoint
Phd1 and Phd3 are differentially expressed in Phd2–/– renal interstitia...
(A) Results from multiplex fluorescent ISH studies using formalin-fixed, paraffin-embedded kidney tissue sections from Foxd1-mT/mG-Phd2–/– mice detecting Epo (blue signal), EGFP (green signal), and Phd1 or Phd3 transcripts (red signal). Shown are representative images; blue arrowheads depict EGFP+Epo+Phd1– cells, purple arrowheads depict EGFP+Epo+Phd1+ or EGFP+Epo+Phd3+ cells, and orange arrowheads point toward EGFP+Epo–Phd1+ or EGFP+Epo–Phd3+ cells. Scale bar: 10 μm. Quantification of cells is shown in the right panels (n = 3 each group). Data are represented as mean ± SEM. (B) Schematic depicting the role of individual PHDs in the regulation of REPC number and renal EPO output. EPO-producing cells are indicated by orange and burgundy red color. Renal interstitial cells that do not produce EPO are indicated by green. Renal tubules are depicted by gray.