Healthy Kidneys: Key Oxygen Sensors of the Body

The Kidneys Serve as Key Oxygen Sensors of the Body That Lead to Increased Erythropoiesis2,11

Healthy Normoxia Rep Cells Healthy Hypoxia Rep Cells Healthy Normoxia Rep Cells Healthy Hypoxia Rep Cells

EPO=erythropoietin; Na+=sodium; O2=oxygen; REP=renal erythropoietin-producing.

EPO=erythropoietin; Na+=sodium; O2=oxygen; REP=renal erythropoietin-producing.

  • The kidneys maintain a finely tuned balance of oxygen supply and demand, such that this region is normally in a state of near-hypoxia12,13
    • Any slight decrease in oxygen supply—such as in anemia—results in hypoxia1,12,13
  • Because of this finely tuned balance, the kidneys are able to sense and respond to small changes in blood oxygen supply12
  • When the kidneys detect hypoxia, the renal erythropoietin-producing cells, or REP cells, located in the outer medulla and cortex, switch to the "ON" (active, EPO-producing) state2,11,14
  • Under normoxic conditions, when the oxygen supply is sufficient, the majority of REP cells are in the “OFF” (resting, non–EPO-producing) state14,15

A state of near-hypoxia

  • Kidneys have high oxygen demand, largely driven by tubular sodium reabsorption16,17
  • Due to the kidneys’ unique vasculature, this high demand is barely matched by the oxygen supply in the outer medulla12,13
  • This causes healthy kidneys to be sensitive to any decrease in oxygen supply12,13

REP cells

  • Renal erythropoietin-producing (REP) cells are specialized cells in the kidneys2,11
  • REP cells sense oxygen levels in their immediate environment to regulate the production of EPO2,11
  • When REP cells detect insufficient oxygen to meet the kidney's needs (hypoxia), they turn on to produce EPO2,11

The Oxygen-sensing Mechanism Relies on the HIF Protein1,2

  • A key component of the oxygen-sensing mechanism in REP cells is the HIF protein1,2
  • HIF is a transcription factor that consists of α and β subunits. It is responsible for regulating the expression of genes involved in erythropoiesis1,7
Healthy Normoxia Healthy Hypoxia

HIF=hypoxia-inducible factor; PH=prolyl hydroxylase; VHL=von Hippel-Lindau.

Normoxia Healthy Normoxia Healthy Hypoxia

HIF=hypoxia-inducible factor; PH=prolyl hydroxylase; VHL=von Hippel-Lindau.

Hypoxia
  • In the presence of sufficient oxygen, HIF-α is hydroxylated by PH enzymes and tagged for degradation1
  • As a result, HIF signaling does not take place, and EPO is not produced1
  • Under hypoxic conditions, hydroxylation of HIF-α does not occur1
  • HIF-α dimerizes with HIF-β to activate target gene expression1,18,19
  • As a result, REP cells increase production of EPO which stimulates erythropoiesis and restores blood oxygen levels1,18

HIF Signaling Regulates EPO Production and Iron Metabolism1,20,21

HIF Signaling Regulates EPO Production and Iron Metabolism

Based on in vitro and observational studies as well as animal models.

  • Activation of the HIF pathway under hypoxic conditions leads to the expression of multiple genes involved in erythropoiesis, resulting in1,18,20,21:
    • Increased endogenous EPO production
    • Improved iron absorption, mobilization, and transport
  • This process allows for a balanced supply of the critical factors required for coordinated erythropoiesis1,15,20,21

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