期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 5, 页码 1926-1938出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI83551
关键词
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资金
- Krick-Brooks chair in Nephrology
- NIH [R01-DK101791, R01-DK081646, R01-DK080821, R01-DK56942]
- Department of Veterans Affairs Merit Award [1I01BX002348]
- Stockholm County Council
- Karolinska Institutet
- Vanderbilt's Diabetes Research and Training Center [P30-DK20593]
- Digestive Disease Research Center Cores [P30-DK058404]
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.
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