Affiliation:
1. Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
2. Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland
3. Department of Physiology, Emory University School of Medicine, Atlanta, Georgia
Abstract
α-Ketoglutarate (α-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 α-KG binding to the OXGR1. To determine the signaling pathway(s) by which α-KG stimulates Cl− absorption, we examined α-KG-stimulated Cl− absorption in isolated perfused mouse CCDs. α-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 α-KG stimulates Cl− absorption through PKC. If so, PKC agonists should mimic, whereas PKC inhibitors should abolish, α-KG-stimulated Cl− absorption. Like α-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), Ca2+ chelators (BAPTA, 10–20 μM), or PKC-α or -δ gene ablation eliminated α-KG-stimulated Cl− absorption. We have shown that STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) gene ablation increases urinary α-KG excretion, renal pendrin abundance, and CCD Cl− absorption. However, in SPAK null CCDs, Cl− absorption was not activated further by luminal α-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, α-KG stimulates pendrin-dependent Cl−/[Formula: see text] exchange through a mechanism dependent on PKC and Ca2+ that involves PKC-α and PKC-δ.
Publisher
American Physiological Society
Cited by
9 articles.
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