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SDF1 induction by acidosis from principal cells regulates intercalated cell subtype distribution
The Journal of Clinical Investigation
|October 31, 2015
Summary
Principal cells in the kidney
Area of Science:
- Nephrology
- Cell Biology
- Physiology
Background:
- The kidney's cortical collecting duct (CCD) has principal cells for ion/water transport and intercalated cells (ICs) for acid-base balance.
- Two IC types exist: acid-secreting α-ICs and HCO3-secreting β-ICs. Chronic acidosis shifts this balance towards α-ICs.
Purpose of the Study:
- To investigate the molecular mechanisms underlying IC subtype changes in response to acidosis.
- To identify signaling pathways involved in regulating ICs within the CCD.
Main Methods:
- Quantitative PCR arrays to assess gene expression changes in kidney tissue and isolated CCDs.
- Functional studies using isolated perfused rabbit CCDs to measure ion secretion.
- Genetic manipulation in mice (IC-specific and whole-cell deletion of Cxcr4 and Hif1a) to assess in vivo effects.
Main Results:
- Acidosis upregulates Stromal cell-Derived Factor 1 (SDF1/CXCL12) mRNA in the kidney cortex and CCD.
- Exogenous SDF1 and acidic conditions increase H+ secretion and decrease HCO3- secretion in CCDs, effects blocked by CXCR4 inhibition.
- Diet-induced acidosis in mice increases α-ICs and decreases β-ICs; this is prevented by Cxcr4 deletion in ICs.
- HIF1α regulates SDF1 transcription in principal cells; HIF1α deletion in all CCD cells, but not just ICs, prevents acidosis-induced IC alterations.
Conclusions:
- Kidney principal cells sense acidosis and produce SDF1, which acts on adjacent ICs via CXCR4.
- This paracrine signaling pathway mediates the adaptive shift in IC subtypes during chronic acidosis.
- HIF1α plays a crucial role in mediating the transcriptional response of principal cells to acidosis, leading to SDF1 production.
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