| First Author | Lazo-Fernandez Y | Year | 2018 |
| Journal | Am J Physiol Renal Physiol | Volume | 315 |
| Issue | 1 | Pages | F7-F15 |
| PubMed ID | 29412702 | Mgi Jnum | J:280485 |
| Mgi Id | MGI:6368889 | Doi | 10.1152/ajprenal.00576.2017 |
| Citation | Lazo-Fernandez Y, et al. (2018) alpha-Ketoglutarate stimulates pendrin-dependent Cl(-) absorption in the mouse CCD through protein kinase C. Am J Physiol Renal Physiol 315(1):F7-F15 |
| abstractText | alpha-Ketoglutarate (alpha-KG) is a citric acid cycle intermediate and a glutamine catabolism product. It is also the natural ligand of 2-oxoglutarate receptor 1 (OXGR1), a Gq protein-coupled receptor expressed on the apical membrane of intercalated cells. In the cortical collecting duct (CCD), Cl(-)/[Formula: see text] exchange increases upon alpha-KG binding to the OXGR1. To determine the signaling pathway(s) by which alpha-KG stimulates Cl(-) absorption, we examined alpha-KG-stimulated Cl(-) absorption in isolated perfused mouse CCDs. alpha-KG increased electroneutral Cl(-) absorption in CCDs from wild-type mice but had no effect on Cl(-) absorption in pendrin knockout mice. Because Gq protein-coupled receptors activate PKC, we hypothesized that alpha-KG stimulates Cl(-) absorption through PKC. If so, PKC agonists should mimic, whereas PKC inhibitors should abolish, alpha-KG-stimulated Cl(-) absorption. Like alpha-KG, PKC agonist (phorbol-12,13-dibutyrate, 500 nM) application increased Cl(-) absorption in wild-type but not in pendrin null CCDs. Moreover, PKC inhibitors (2.5 mM GF109203X and 20 nM calphostin C), Ca(2+) chelators (BAPTA, 10-20 muM), or PKC-alpha or -delta gene ablation eliminated alpha-KG-stimulated Cl(-) absorption. We have shown that STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) gene ablation increases urinary alpha-KG excretion, renal pendrin abundance, and CCD Cl(-) absorption. However, in SPAK null CCDs, Cl(-) absorption was not activated further by luminal alpha-KG application nor was Cl(-) absorption reduced with the PKC inhibitor GF109203 . Thus SPAK gene ablation likely acts through a PKC-independent pathway to produce a chronic adaptive increase in pendrin function. In conclusion, alpha-KG stimulates pendrin-dependent Cl(-)/[Formula: see text] exchange through a mechanism dependent on PKC and Ca(2+) that involves PKC-alpha and PKC-delta. |
