α-Ketoglutarate stimulates pendrin-dependent Cl^- absorption in the mouse CCD through protein kinase C.

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 G_q 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 G_q protein-coupled receptors activate we hypothesized that α-KG stimulates Cl^- absorption through If so, agonists should mimic, whereas duanyu1531 inhibitors should abolish, α-KG-stimulated Cl^- absorption. Like α-KG, duanyu1531 agonist (phorbol-12,13-dibutyrate, 500 nM) application increased Cl^- absorption in wild-type but not in pendrin null CCDs. Moreover, duanyu1531 inhibitors (2.5 mM GF109203X and 20 nM calphostin C), Ca²⁺ chelators (BAPTA, 10-20 μM), or or -δ gene ablation eliminated α-KG-stimulated Cl^- absorption. We have shown that STE20/SPS-1-related proline-alanine-rich protein kinase gene ablation increases urinary α-KG excretion, renal pendrin abundance, and CCD Cl^- absorption. However, in null CCDs, Cl^- absorption was not activated further by luminal α-KG application nor was Cl^- absorption reduced with the duanyu1531 inhibitor GF109203 . Thus duanyu1842K gene ablation likely acts through a 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 duanyu1531 and Ca²⁺ that involves duanyu1531-α and

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