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Synergetic Effects of Hypokalemia and Volume Contraction Combine to Drive Paracrine Secretion of αKG

Hypokalemic, intravascular volume contraction stimulates the release of angiotensin II (AngII), but not aldosterone. The adaptive mechanisms that mitigate this phenotype to restore electrolyte balance and blood pressure are not well defined. Alpha‐ketoglutarate (αKG) is an end product of glutamate deamination, a component of the ammoniagenesis pathway occurring in the renal proximal tubule (PT). αKG found in the pro‐urine binds to its G‐protein coupled receptor, OXGR1, localized to the apical membrane of Pendrin expressing intercalated cells. Induction of αKG/OXGR1 signaling increases Pendrin mediated Cl−/HCO3− exchange. Pendrin is also a component of a multi‐gene transport system in non A‐type intercalated cells, along with the bicarbonate‐dependent Na+/Cl− transporter, NDCBE, which mediates electroneutral NaCl reabsorption in exchange for bicarbonate. We recently reported αKG production and secretion are stimulated in SPAK null mice, which are unable to phosphoactivate the sodium chloride cotransporter (NCC). The physiological signal(s) stimulating the production of αKG remains unclear. Interestingly, these mice are volume contracted with increased renin activity, have low plasma K+ levels, and display increased expression of Pendrin and NDCBE. Here we tested the hypothesis that αKG production and secretion are stimulated through the synergistic effects of hypokalemia and volume contraction induced AngII signaling. We tested this hypothesis in vivo using WT mice exposed to dietary and pharmacological manipulations and in vitro using the LLCPK‐1 PT cell line. When WT mice were challenged with a low K+ diet, αKG release did not increase acutely, despite rapid development of hypokalemia, indicating that hypokalemia is not sufficient. By contrast, the angiotensin II receptor (AT1) antagonist, losartan, completely blocked αKG secretion in a mouse model of hydrochlorothiazide‐induced αKG secretion. However, we could not conclude that AngII is sufficient to trigger αKG secretion. Using LLCPK‐1 cells, we tested the direct and independent effects of AngII and low extracellular K+ on αKG secretion. Remarkably, a marked increase in αKG secretion was only observed when extracellular K+ was reduced (2.5 mM) and combined with AngII (100 nM), contrasting the absence of stimulation by either agent alone. Quantitative transcript measurements of the ammoniagenesis enzymes, and the apical membrane transporter for αKG efflux, OAT10, provide a mechanistic explanation. We found low K+ increased the enzymes that produce αKG, while AngII increased OAT10. Thus, synergetic effects of two physiological stimuli combine to drive αKG secretion by separately activating αKG synthesis and transport. Based on these observations, we propose that the aKG/OXGR1 paracrine system acts as a physiological coincidence detector that is activated in the combined states of hypokalemia and hypovolemia resulting in pendrin/NDCBE‐mediated electroneutral salt reabsorption (K+ sparing) and bicarbonate secretion, and thereby limits urinary losses of Na+, Cl−, and K+. Such a system is ideally suited to normalize electrolyte balance and the intravascular volume in hypokalemic volume contraction, which commonly occur with protracted vomiting, or in fasting states.