@article {48300,
	title = {Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin.},
	journal = {The Journal of Clinical Investigation},
	volume = {126},
	year = {2016},
	month = {2016 May 02},
	pages = {1926-38},
	abstract = {<p>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.</p>
},
	issn = {1558-8238},
	doi = {10.1172/JCI83551},
	author = {Kobayashi, Hanako and Liu, Qingdu and Binns, Thomas C and Urrutia, Andres A and Davidoff, Olena and Kapitsinou, Pinelopi P and Pfaff, Andrew S and Olauson, Hannes and Wernerson, Annika and Fogo, Agnes B and Fong, Guo-Hua and Gross, Kenneth W and Haase, Volker H}
}
