α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism

Tokonami, Natsuko; Morla, Luciana; Centeno, Gabriel; Mordasini, David; Ramakrishnan, Suresh Krishna; Nikolaeva, Svetlana; Wagner, Carsten A.; Bonny, Olivier; Houillier, Pascal; Doucet, Alain; Firsov, Dmitri

doi:10.1172/jci67562

Cited by 67 publications

(95 citation statements)

References 23 publications

(36 reference statements)

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“…The carboxylate tail of αKG has a predicted pK a of 4.28 ± 1.27 (closely matching the experimental pK a of 4.4) 41 , indicating that it would be mostly deprotonated in solution at pH values ranging from 6.0 to 7.4. However, upon binding to LDHA, the carboxylate tail of αKG becomes protonated whereupon it is predicted to form a hydrogen bond with Q100 (Fig.…”

Section: Resultssupporting

confidence: 70%

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.

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Section: Resultssupporting

confidence: 70%

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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“…-/-mice, we [176] showed that apical but not basolateral αKG acts through OXGR1 in acid-base stress. It is well known that acute acidosis activates, whereas alkalosis inhibits, NaCl reabsorption in the proximal tubule and ascending limb [177] .…”

Section: Regulation Of Sodium Transport In the Distal Nephron By "Novmentioning

confidence: 59%

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

Morla

Edwards

Crambert

2016

WJBC

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The renal handling of Na + balance is a major determinant of the blood pressure (BP) level. The inability of the kidney to excrete the daily load of Na + represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part (i.e ., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na + excretion and are the target of many different regulatory processes that modulate Na + retention more or less efficiently. G-protein coupled receptors (GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na + absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na + excretion, this review also highlights the complexity of these different pathways, and the connections between them.

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“…In this issue of the JCI, the study by Tokonami et al (13) adds the newest chapter to the emerging view of the distal nephron and collecting duct, with the discovery of a paracrine regulatory loop between the proximal and distal nephron that controls acid-base balance. They found that OXGR1 expressed in type B and non-A-non-B intercalated cells of the distal nephron and collecting duct can detect αKG secreted by proximal tubule and loop segments and regulate Cl --dependent type B intercalated cells, which upon functional coupling with pendrin performs electroneutral NaCl reabsorption (6).…”

Section: Discussionmentioning

confidence: 99%

“…The new data indicate that αKG directly controls intercalated cell electroneutral NaCl reabsorption and suggest that OXGR1-mediated distal NaCl reabsorption is required to compensate for the altered proximal reabsorption of salt under a body acid-base challenge. (13). Subsequently, elegant in vitro tubule microperfusion studies demonstrated that luminal activation of OXGR1 by αKG stimulated pendrin activity (HCO 3 -secretion) and electroneutral reabsorption of NaCl by type B and non-A-non-B intercalated cells.…”

mentioning

confidence: 99%

“…Subsequently, elegant in vitro tubule microperfusion studies demonstrated that luminal activation of OXGR1 by αKG stimulated pendrin activity (HCO 3 -secretion) and electroneutral reabsorption of NaCl by type B and non-A-non-B intercalated cells. This novel renal control mechanism was shown to be functionally important and relevant in vivo, since mice devoid of OXGR1 exhibited a reduced capacity to maintain body acid-base equilibrium under base load conditions (13).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial TCA cycle intermediates regulate body fluid and acid-base balance

Peti‐Peterdi

2013

J. Clin. Invest.

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α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism

Cited by 67 publications

References 23 publications

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

Mitochondrial TCA cycle intermediates regulate body fluid and acid-base balance

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