Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin
Navid M. Farsijani, Qingdu Liu, Hanako Kobayashi, Olena Davidoff, Feng Sha, Joachim Fandrey, T. Alp Ikizler, Paul M. O’Connor, Volker H. Haase
Navid M. Farsijani, Qingdu Liu, Hanako Kobayashi, Olena Davidoff, Feng Sha, Joachim Fandrey, T. Alp Ikizler, Paul M. O’Connor, Volker H. Haase
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Research Article Nephrology

Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin

Abstract

The adult kidney plays a central role in erythropoiesis and is the main source of erythropoietin (EPO), an oxygen-sensitive glycoprotein that is essential for red blood cell production. Decreases of renal pO2 promote hypoxia-inducible factor 2–mediated (HIF-2–mediated) induction of EPO in peritubular interstitial fibroblast-like cells, which serve as the cellular site of EPO synthesis in the kidney. It is not clear whether HIF signaling in other renal cell types also contributes to the regulation of EPO production. Here, we used a genetic approach in mice to investigate the role of renal epithelial HIF in erythropoiesis. Specifically, we found that HIF activation in the proximal nephron via induced inactivation of the von Hippel–Lindau tumor suppressor, which targets the HIF-α subunit for proteasomal degradation, led to rapid development of hypoproliferative anemia that was associated with a reduction in the number of EPO-producing renal interstitial cells. Moreover, suppression of renal EPO production was associated with increased glucose uptake, enhanced glycolysis, reduced mitochondrial mass, diminished O2 consumption, and elevated renal tissue pO2. Our genetic analysis suggests that tubulointerstitial cellular crosstalk modulates renal EPO production under conditions of epithelial HIF activation in the kidney.

Authors

Navid M. Farsijani, Qingdu Liu, Hanako Kobayashi, Olena Davidoff, Feng Sha, Joachim Fandrey, T. Alp Ikizler, Paul M. O’Connor, Volker H. Haase

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Figure 2

Renal epithelial Vhl inactivation results in anemia.

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Renal epithelial Vhl inactivation results in anemia. Hematologic effects...
Hematologic effects of Pax8-rtTA–mediated inactivation of Vhl in the absence of hepatic EPO induction. (A) Genomic PCR analysis of DNA isolated from kidney, liver, and tail of P8;Vhlfl/fl Epofl/fl and Cre– control mice. (B) Hct, Hb, and rbc counts in P8;Vhlfl/fl Epofl/fl, P8;Epofl/fl, and control (n = 5 each). (C) Corresponding reticulocyte counts (Retic.) and RPI in P8;Vhlfl/fl Epofl/fl and control mice (n = 5 each). (D) Relative renal and hepatic Epo mRNA levels in P8;Vhlfl/fl Epofl/fl and control mice (top panel, n = 5 each) and P8;Epofl/fl (bottom panel; n = 6 kidney samples and n = 3 liver samples) in comparison with control mice (n = 8 kidney samples and n = 3 liver samples). (E) Schematic depicting cellular contributions to sEPO levels in P8;Epofl/fl single mutants (left panel) and P8;Vhlfl/fl Epofl/fl double mutants (right panel). Red x indicates Cre-mediated gene inactivation; black x indicates that the Epo gene is not transcribed in tubular epithelial cells. The tildes indicate that Epo is not detectable in hepatocytes under baseline conditions. EPO production in the liver is no longer increased in P8;Vhlfl/fl Epofl/fl double mutants (right panel). **P < 0.01; ***P < 0.001, 1-way ANOVA followed by Dunnett’s post hoc analysis (B); unpaired 2-tailed Student’s t test (C and D). Shown are mean values ± SEM. 2-lox, nonrecombined conditional Vhl or Epo allele; 1-lox, recombined allele. See Supplemental Figure 2 for additional information.