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Intrarenal Metabolite (α‐Ketoglutarate) Signaling Pathway Is Activated by Hnf1α‐Mediated Transcriptional Regulation of OAT10

We recently discovered an unusual pathway that couples alterations in intermediate metabolism to salt retention. We found that thiazide diuretics or genetic loss of NCC phosphorylation (SPAK KO) or hypokalemia with intravascular volume contraction activates the synthesis and secretion of α‐ketoglutarate (αKG) from the proximal tubule (PT). αKG is then delivered in the tubular fluid to the distal nephron where it activates its cognate G‐protein coupled receptor, OxGR1, and this stimulates a salt reabsorption network (Pendrin/NDCBE) as a part of a homeostatic response that limits urinary sodium and potassium loss. Hypokalemia appears to stimulate αKG synthesis, whereas volume contraction stimulates αKG transport through angiotensin II (AngII). In the present study, we explore the mechanism by which αKG secretion is activated.