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SDF1 induction by acidosis from principal cells regulates intercalated cell subtype distribution
George J. Schwartz, … , Dominique Eladari, Qais Al-Awqati
George J. Schwartz, … , Dominique Eladari, Qais Al-Awqati
Published October 26, 2015
Citation Information: J Clin Invest. 2015;125(12):4365-4374. https://doi.org/10.1172/JCI80225.
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Research Article Nephrology

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

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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 HIF1α. 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.

Authors

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

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Figure 2

ISH of SDF1 in mouse kidney cortex and medulla.

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ISH of SDF1 in mouse kidney cortex and medulla.
(A) Images of the CCD an...
(A) Images of the CCD and S1 segment of the proximal tubule. (B) Images of OMCDs. Note the thick ascending limb, which shows a high brown background but not much SDF1 staining. (C) Image of the S1 proximal tubule connecting with the glomerulus. Images were taken from mice fed a normal diet or a 2-day acid diet. Representative samples from 2 independent studies. Arrows in the CCD and OMCD images indicate heterogeneous, lower-intensity staining in different cells of these structures compared with more homogeneous staining in the S1 segment. Original magnification, ×600. G, glomerulus; PT, proximal tubule; ThAL, thick ascending limb.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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