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 4

Epithelial Vhl ablation alters renal metabolism.

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Epithelial Vhl ablation alters renal metabolism. Differential regulation...
Differential regulation of genes involved in glycolysis (A), fatty acid metabolism (B), and renal transport function (C) by genome-scale RNA expression profiling in kidneys from P8;Vhlfl/fl and Cre– control mice (n = 4 each). Shown are differentially regulated metabolic genes that were either significantly up- or downregulated (≥ 1.5-fold). Color intensity is scaled within each row so that the highest expression value corresponds to bright red and the lowest to bright green. Each column represents expression levels in an individual kidney. (D) Verification of gene-expression analysis by quantitative PCR for key target genes from P8;Vhlfl/fl and Cre– control mice (n = 6 each). (E) Assessment of renal glucose metabolism by quantification of 2-DG uptake in renal medulla from P8;Vhlfl/fl Epofl/fl and control mice (n = 3 each). (F) Renal M3 pyruvate and M3 lactate concentrations in total kidney extracts from P8;Vhlfl/fl Epofl/fl and control mice (n = 3 each). *P < 0.05; **P < 0.01; ***P < 0.001, unpaired 2-tailed Student’s t test. Shown are mean values ± SEM.