Editing Α-Ketoglutaric acid (section)

===Bioactions of α-Ketoglutarate===
====OXGR1 receptor-dependent bioactions====
OXGR1 (also known as GPR99) is a [[G protein-coupled receptor]], i.e., a [[Receptor (biochemistry)|receptor]] located on the [[Cell membrane|surface membrane of cells]] that binds certain [[Ligand (biochemistry)|ligands]] and is thereby stimulated to activate [[G proteins]] that elicit pre-programmed responses in their parent cells. OXRG1 was identified as a receptor for: '''a)''' α-ketoglutarate in 2004;<ref name="pmid36919698">{{cite journal | vauthors = Zeng YR, Song JB, Wang D, Huang ZX, Zhang C, Sun YP, Shu G, Xiong Y, Guan KL, Ye D, Wang P | title = The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response | journal = The Journal of Clinical Investigation | volume = 133 | issue = 6 | pages = | date = March 2023 | pmid = 36919698 | pmc = 10014103 | doi = 10.1172/JCI160463 | url = }}</ref><ref name="pmid38448252">{{cite journal | vauthors = Ye D, Wang P, Chen LL, Guan KL, Xiong Y | title = Itaconate in host inflammation and defense | journal = Trends in Endocrinology and Metabolism | volume = | issue = | pages = | date = March 2024 | pmid = 38448252 | doi = 10.1016/j.tem.2024.02.004 | url = }}</ref> '''b)''' three [[leukotrienes]] viz., [[leukotriene E4|leukotrienes E4]], [[leukotriene C4|C4]], and [[Leukotriene D4|D4]] in 2013.<ref name="pmid23504326">{{cite journal | vauthors = Kanaoka Y, Maekawa A, Austen KF | title = Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand | journal = The Journal of Biological Chemistry | volume = 288 | issue = 16 | pages = 10967–72 | date = April 2013 | pmid = 23504326 | pmc = 3630866 | doi = 10.1074/jbc.C113.453704 | doi-access = free | url = }}</ref><ref name="pmid31135881">{{cite journal | vauthors = Sasaki F, Yokomizo T | title = The leukotriene receptors as therapeutic targets of inflammatory diseases | journal = International Immunology | volume = 31 | issue = 9 | pages = 607–615 | date = August 2019 | pmid = 31135881 | doi = 10.1093/intimm/dxz044 | url = }}</ref> and '''c)''' [[itaconate]] in 2023.<ref name="pmid36919698"/><ref name="pmid38448252"/> These ligands have the following relative potencies in stimulating responses in OXGR1-bearing cells (Note that LTE4 can stimulate OXGR1 at concentrations far lower than those of the other four ligands):

:::LTE4 >> LTC4 = LTD4 > α-ketoglutarate = itaconate.

It may be difficult to determine if an OXGR1-stimulating agent elicits a functional response by activating OXGR1 as opposed to some other mechanism. To make this distinction, studies have shown that the action of an OXGR1-activating agent on cultured cells, cultured tissues, or animals does not occur or is reduced when these cells, tissues, or animals have been altered so that they do not express or express greatly reduced levels of the OXGR1 protein,<ref name="pmid36919698"/><ref name="pmid38448252"/><ref name="pmid23504326"/><ref name="pmid34179130">{{cite journal | vauthors = Guerrero A, Visniauskas B, Cárdenas P, Figueroa SM, Vivanco J, Salinas-Parra N, Araos P, Nguyen QM, Kassan M, Amador CA, Prieto MC, Gonzalez AA | title = α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions | journal = Frontiers in Cardiovascular Medicine | volume = 8 | issue = | pages = 644797 | date = 2021 | pmid = 34179130 | pmc = 8220822 | doi = 10.3389/fcvm.2021.644797 | doi-access = free | url = }}</ref> or when their actions are inhibited by an OXGR1 [[receptor antagonist]]s. OXGR1 is inhibited by [[Montelukast]], a well-known inhibitor of the [[cysteinyl leukotriene receptor 1]], i.e., the receptor for LTD4, LTC4, and LTE4. Montelukast also blocks the binding of these leukotrienes to, and thereby inhibits their activation of, OXGR1. One study presented evidence suggesting that α-ketoglutarate binds to OXGR1. It is assumed that Montelukast similarly blocks α-ketoglutarate's binding to,  and thereby inhibits its activation of OXGR1.<ref name="pmid23504326"/><ref name="pmid34179130"/>

====Kidney functions====
The [[pendrin]] protein promotes the [[electroneutral exchange]] of tissue [[chloride]] (Cl<sup>−</sup>) for urinary [[bicarbonate]] (HCO<sub>3</sub><sup>−</sup>) in the apical surfaces (i.e., surfaces facing the urine) of the kidney's renal β-intercalated cells (also termed type B intercalated cells) and non-α non-β intercalated cells (also	termed non-A non-B intercalated cells) in the kidney's [[collecting duct system]] (i.e., CDS).<ref name="pmid38110744">{{cite journal | vauthors = Brazier F, Cornière N, Picard N, Chambrey R, Eladari D | title = Pendrin: linking acid base to blood pressure | journal = Pflügers Archiv | volume = 476 | issue = 4 | pages = 533–543 | date = April 2024 | pmid = 38110744 | doi = 10.1007/s00424-023-02897-7 | url = }}</ref> A study in mice found that OXGR1 colocalizes with [[pendrin]] in the [[Collecting duct system#Intercalated cells|β-intercalated cells and non-α non-β intercalated cells]] lining the [[tubules]] of their kidney's CDS. The intercalated cells in the CDS tubules isolated from mice used pendrin in cooperation with the [[electroneutral sodium bicarbonate exchanger 1]] protein to mediate the Cl<sup>−</sup> for HCO<sub>3</sub><sup>−</sup> exchange. α-Ketoglutarate stimulated the rate of this exchange in CDS tubules isolated from control mice (i.e., mice that had the ''Oxgr1'' gene and protein) but not in CDS tubules isolated from ''Oxgr1'' [[gene knockout]] mice (i.e., mice that lacked the ''Oxgr1'' gene and protein). This study also showed that the α-ketoglutarate in the blood of mice filtered through their kidney's [[glomeruli]] into the [[proximal tubules]] and [[loops of Henle]] where it was reabsorbed. Mice drinking water with a [[Basic (chemistry)|basic]] [[pH]] (i.e., >7) due to the addition of [[sodium bicarbonate]] and mice lacking the ''Oxgr1'' gene and protein who drink water without sodium bicarbonate had urines that were more basic (i.e., pH about 7.8) and contained higher levels of urinary α-ketoglutarate than control mice drinking water without this additive. Furthermore, ''Oxgr1'' gene knockout mice drinking sodium bicarbonate-rich water developed [[metabolic alkalosis]] (body tissue pH levels higher than normal) that was associated with blood bicarbonate levels significantly higher and blood chloride levels significantly lower than those in control mice drinking the sodium bicarbonate-rich water.<ref name="pmid23934124"/> Several other studies confirmed these findings and reported that cells in the proximal tubules of mice synthesize α-ketoglutarate and either broke it down thereby reducing its urine levels or secreted it into the tubules' lumens thereby increasing its urine levels.<ref name="pmid28771454">{{cite journal | vauthors = Grimm PR, Welling PA | title = α-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor, Oxgr1 | journal = Current Opinion in Nephrology and Hypertension | volume = 26 | issue = 5 | pages = 426–433 | date = September 2017 | pmid = 28771454 | doi = 10.1097/MNH.0000000000000353 | url = }}</ref> Another study showed that '''a)''' ''[[In silico]]'' [[computer simulation]]s strongly suggested that α-ketoglutarate bound to mouse OXGPR1; '''b)''' suspensions of canal duct cells isolated from the collecting ducts, loops of Henle, [[Vasa recta (kidney)|vasa recta]], and [[interstitium]] of mouse kidneys raised their cytosolic ionic calcium, i.e., Ca<sup>2+</sup> levels in response to α-ketoglutarate but this response (which is an indicator of cell activation) was blocked by pretreating the cells with Montelukast; and '''c)''' compared to mice not treated with [[streptozotocin]], streptozotocin-induced diabetic mice (an [[animal disease model]] of [[diabetes]]) urinated only a small amount of the ionic sodium ({{chem2|Na+}}) that they drank or received by intravenous injections; Montelukast reversed this defect in the streptozotocin-pretreated mice.<ref name="pmid34179130"/> These results indicate that in mice: '''a)''' α-ketoglutarate stimulates kidney OXGR1 to activate pendrin-mediated reabsorption of sodium and chloride by type B and non-A–non-B intercalated cells; '''b)''' high [[alkaline]] (i.e., sodium bicarbonate) intake produces significant increases in urine pH and α-ketoglutarate levels and impairs secretion of bicarbonate into the CDS tubules' lumens; '''c)''' the [[Acid–base homeostasis|acid–base balance]] (i.e., levels of acids relative to their bases) in the face of high alkali intake depends on the activation of OXGR1 by α-ketoglutarate;<ref name="pmid23934124"/><ref name="pmid28771454"/> '''d)''' alkaline loading directly or indirectly stimulates α-ketoglutarate secretion into the kidney's proximal tubules where further down these tubules it activates OXGR1 and thereby the absorption and secretion of various agents that contribute to restoring a physiologically normal acid-base balance;<ref name="pmid28771454"/> and '''e)''' α-ketoglutarate stimulates OXGR1-bearing CDS cells to raise their levels of cytosolic Ca<sup>2+</sup>) and in diabetic mice (and presumably other conditions involving high levels of blood and/or urine glucose) to increase these cells uptake of {{chem2|Na+}}.<ref name="pmid23934124"/><ref name="pmid34179130"/><ref name="pmid38110744"/><ref name="pmid28771454"/>

====Resistance exercise, obesity, and muscle atrophy====
Resistance exercise is exercising a muscle or muscle group against external resistance (see [[strength training]]). Studies have found that: '''a)''' mice feeding on a high fat or normal diet and given the resistance exercise of repeatedly climbing up a 1 [[meter]] ladder for 40 minutes had higher levels of α-ketoglutarate in their blood and seven muscles than non-exercising mice feeding respectively on the high fat or normal diet; '''b)''' mice conducting ladder climbing for several weeks and eating a high fat diet developed lower fat tissue masses and higher lean tissue masses than non-exercising mice on this diet; '''c)''' mice not in exercise training fed α-ketoglutarate likewise developed lower fat tissue and higher lean tissue masses than α-ketoglutarate-unfed, non-exercising mice; '''d)''' OXGR1 was strongly expressed in the mouse [[Renal medulla|adrenal gland inner medullas]] and either resistance training or oral α-ketoglutarate increased this tissue's levels of the [[mRNA]] that is responsible for the synthesis of OXGR1; '''e)''' α-ketoglutarate stimulated [[chromaffin cells]] isolated from mouse adrenal glands to release [[epinephrine]] but reduction of these cells' OXGR1 levels by [[small interfering RNA]] reduced this response; '''f)''' α-ketoglutarate increased the blood serum levels of epinephrine in mice expressing OXGR1 but not in ''Oxgr1'' gene knockout mice (i.e., mice lacking the ''OXGR1'' gene and protein); '''g)''' mice on the high fat diet challenged with α-ketoglutarate increased their blood serum levels of epinephrine and developed lower fat tissue masses and higher lean tissue masses but neither ''OXGR1'' gene knockout mice nor mice that had only their adrenal glands' ''OXGR1'' gene knocked out showed these responses; and '''h)''' ''OXGR1'' gene knockout mice fed the high fat diet developed muscle protein degradation, muscle [[atrophy]] (i.e., wasting), and falls in body weight whereas control mice did not show these fat diet-induced changes. These findings indicate that in mice resistance exercise increases muscle production as well as serum levels of α-ketoglutarate which in turn suppresses diet-induced obesity (i.e., low body fat and high lean body masses) at least in part by stimulating the OXGR1 on adrenal gland chromaffin cells to release epinephrine.<ref name="pmid32104923"/><ref name="pmid35507647"/><ref name="pmid28939592">{{cite journal | vauthors = Cai X, Yuan Y, Liao Z, Xing K, Zhu C, Xu Y, Yu L, Wang L, Wang S, Zhu X, Gao P, Zhang Y, Jiang Q, Xu P, Shu G | title = α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway | journal = FASEB Journal | volume = 32 | issue = 1 | pages = 488–499 | date = January 2018 | pmid = 28939592 | pmc = 6266637 | doi = 10.1096/fj.201700670R | doi-access = free | url = }}</ref> Another study reported that middle‐aged, i.e., 10‐month‐old, mice had lower serum levels of α-ketoglutarate than 2‐month‐old mice. Middle aged mice fed a high fat diet gained body weight and fat mass in the lower parts of their bodies and had impaired glucose tolerance as defined in glucose tolerance tests. Adding α-ketoglutarate to the drinking water of these mice inhibited the development of these changes. These results suggest that drinking the α-ketoglutarate-rich water replenished the otherwise diminished supplies of α-ketoglutarate in middle aged mice; the replenished supply of α-ketoglutarate thereby became available to suppress obesity and improve glucose tolerance.<ref name="pmid31691468">{{cite journal | vauthors = Tian Q, Zhao J, Yang Q, Wang B, Deavila JM, Zhu MJ, Du M | title = Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice | journal = Aging Cell | volume = 19 | issue = 1 | pages = e13059 | date = January 2020 | pmid = 31691468 | pmc = 6974731 | doi = 10.1111/acel.13059 | url = }}</ref> Finally, a study in rats feed a low fat or high fat diet for 27 weeks and drinking α-ketoglutarate-rich water for the last 12 weeks of this 27 week period decreased their fat issue masses and increased their whole-body insulin sensitivity as defined in glucose tolerance tests. Rats fed either of these diets but not given α-ketoglutarate-rich water did not show these changes. This study indicates that α-ketoglutarate regulates body fat mass and insulin sensitivity in rats as well as mice.<ref name="pmid31357871">{{cite journal | vauthors = Tekwe CD, Yao K, Lei J, Li X, Gupta A, Luan Y, Meininger CJ, Bazer FW, Wu G | title = Oral administration of α-ketoglutarate enhances nitric oxide synthesis by endothelial cells and whole-body insulin sensitivity in diet-induced obese rats | journal = Experimental Biology and Medicine | volume = 244 | issue = 13 | pages = 1081–1088 | date = October 2019 | pmid = 31357871 | pmc = 6775570 | doi = 10.1177/1535370219865229 | url = }}</ref>