SDF1 induction by acidosis from principal cells regulates intercalated cell subtype distribution

George J. Schwartz, Xiao Bo Gao, Shuichi Tsuruoka, Jeffrey M. Purkerson, Hu Peng, Vivette D'Agati, Nicolas Picard, Dominique Eladari, Qais Al-Awqati

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The nephron cortical collecting duct (CCD) is composed of principal cells, which mediate Na, K, and water transport, and intercalated cells (ICs), which are specialized for acid-base transport. There are two canonical IC forms: acid-secreting α-ICs and HCO3-secreting β-ICs. Chronic acidosis increases α-ICs at the expense of β-ICs, thereby increasing net acid secretion by the CCD. We found by growth factor quantitative PCR array that acidosis increases expression of mRNA encoding SDF1 (or CXCL12) in kidney cortex and isolated CCDs from mouse and rabbit kidney cortex. Exogenous SDF1 or pH 6.8 media increased H+ secretion and decreased HCO3 secretion in isolated perfused rabbit CCDs. Acid-dependent changes in H+ and HCO3 secretion were largely blunted by AMD3100, which selectively blocks the SDF1 receptor CXCR4. In mice, diet-induced chronic acidosis increased α-ICs and decreased β-ICs. Additionally, IC-specific Cxcr4 deletion prevented IC subtype alterations and magnified metabolic acidosis. SDF1 was transcriptionally regulated and a target of the hypoxia-sensing transcription factor HIF1á. IC-specific deletion of Hif1a produced no effect on mice fed an acid diet, as α-ICs increased and β-ICs decreased similarly to that observed in WT littermates. However, Hif1a deletion in all CCD cells prevented acidosis-induced IC subtype distribution, resulting in more severe acidosis. Cultured principal cells exhibited an HIF1α-dependent increase of Sdf1 transcription in response to media acidification. Thus, our results indicate that principal cells respond to acid by producing SDF1, which then acts on adjacent ICs.

Original languageEnglish (US)
Pages (from-to)4365-4374
Number of pages10
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
StatePublished - Dec 2015
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Schwartz, G. J., Gao, X. B., Tsuruoka, S., Purkerson, J. M., Peng, H., D'Agati, V., Picard, N., Eladari, D., & Al-Awqati, Q. (2015). SDF1 induction by acidosis from principal cells regulates intercalated cell subtype distribution. Journal of Clinical Investigation, 125(12), 4365-4374. https://doi.org/10.1172/JCI80225