| First Author | Schwartz GJ | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 12 | Pages | 4365-74 |
| PubMed ID | 26517693 | Mgi Jnum | J:229402 |
| Mgi Id | MGI:5751932 | Doi | 10.1172/JCI80225 |
| Citation | Schwartz GJ, et al. (2015) SDF1 induction by acidosis from principal cells regulates intercalated cell subtype distribution. J Clin Invest 125(12):4365-74 |
| abstractText | 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 alpha-ICs and HCO3-secreting beta-ICs. Chronic acidosis increases alpha-ICs at the expense of beta-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 alpha-ICs and decreased beta-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 HIF1alpha. IC-specific deletion of Hif1a produced no effect on mice fed an acid diet, as alpha-ICs increased and beta-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 HIF1alpha-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. |
