Summary
The proximal tubule cell is the major site of renal ammoniagenesis. Glutamine is the major substrate. Deamidation by mitochondrial glutaminase yields glutamate− and NH +4 (not NH3, as traditionally taught). A second NH +4 ion is obtained by deamination of glutamate− to 2-oxo-glutarate2−. NH +4 preferentially enters the tubule lumen primarily, but probably not exclusively, by non-ionic diffusion of NH3. For each NH3 formed in the cell one H+ ion is left behind. H+ and NH3 are secreted on separate routes, but recombine in the lumen to NH +4 and reach the final urine in this form. This processper se does not net-remove H+ from the organism. For this purpose, the anionic products of ammoniagenesis (2-oxo-glutarate2− and others) have to be converted into neutral compounds (CO2, glucose). This metabolism again takes place usually in the tubule cell. For each negative charge one HCO −3 is formed which enters the peritubular blood. Luminal γ-glutamyl transferase-mediated ammoniagenesis contributes to NH +4 accumulation in the proximal tubule to a small extent. The endproximal NH +4 delivery exceeds the filtered load by a factor of 9. Only 1/3 of it reaches the distal convoluted tubule mainly because NH +4 as such is reabsorbed from the thick ascending limb of Henle's loop by secondary active transport or electrodiffusion. Both processes are energized by the active Na+ transport in this segment. Thereby NH3↔NH +4 is accumulated in the medullary interstitium, which establishes the chemical gradient for non-ionic diffusion of NH3 into the lumen of the collecting ducts. This is favoured by the acidic disequilibrium pH in the lumen of this segment. Secretion of NH3↔NH +4 , probably by non-ionic diffusion, also into the descending limb of the loop is hypothesized to maintain (together with the NH +4 reabsorption in the thick ascending limb) the high interstitial NH3↔NH +4 concentration increasing towards to inner medulla. Thus, the principle of counter current multiplication seems to be involved also in NH +4 excretion.
Zusammenfassung
Hauptort der renalen NH3↔NH +4 -Bildung ist die proximale Tubuluszelle. Glutamin ist das wesentliche Substrat dafür. Die Desamidierung durch die mitochondriale Glutaminase ergibt Glutamat− und NH +4 (und nicht NH3, wie oft behauptet). Ein zweites NH +4 -Ion wird aus der Desaminierung von Glutamat− zu 2-Oxo-Glutarat2− gewonnen. NH +4 gelangt in das Tubuluslumen großteils (aber nicht ausschließlich) in der Form von NH3 (nicht-ionische Diffusion). Für jedes sezernierte NH3 bleibt ein H+-Ion in der Zelle zurück, das separat ins Lumen transportiert wird. Im Lumen wird aus beiden wieder NH +4 gebildet, das dann im Urin ausgeschieden wird. Dieser Prozeßper se entfernt keine H+-Ionen aus dem Körper. Zu diesem Zwecke müssen erst die anionischen Metaboliten, die bei der Ammoniagenese entstehen (2-Oxo-Glutarat2− u.a.), in neutrale Stoffe umgewandelt werden (CO2, Glukose). Dies geschieht ebenfalls, wenn auch nicht notwendigerweise, in der Tubuluszelle. Für jede negative Ladung des Substrats entsteht dabei ein HCO −3 -Ion, das die Zelle auf der Blutseite verläßt. Eine luminale NH +4 -Bildung, katalysiert durch γ-Glutamyltransferase, trägt in geringem Ausmaß zur NH +4 -Anhäufung im Lumen bei. Am Ende des proximalen Konvoluts findet sich 9mal mehr NH3↔NH +4 als im Glomerulusfiltrat. Nur ein Drittel davon erreicht das distale Konvolut, vor allem weil NH +4 als solches im dicken, aufsteigenden Teil der Henleschen Schleife durch Co-Transport oder Elektrodiffusion resorbiert wird. Beide Prozesse erhalten ihre Energie durch den aktiven Na+-Transport in diesem Nephronteil. Dadurch wird NH3↔NH +4 u.a. im medullären Interstitium akkumuliert, so daß ein chemischer Gradient für die nicht-ionische Diffusion von NH3 ins Lumen des Sammelrohrs aufgebaut wird. Begünstigt wird dies auch durch den sauren Disäquilibriums-pH-Wert im Lumen dieses Segments. Es wurde vorgeschlagen, daß NH3↔NH +4 , wohl via nicht-ionische Diffusion, auch in den absteigenden Teil der Henleschen Schleife sezerniert wird, um, zusammen mit der NH +4 -Resorption im aufsteigenden Schleifenteil, die hohe interstitielle NH3↔NH +4 -Konzentration, die markwärts zunimmt, aufrechtzuerhalten. Das Prinzip der Gegenstrom-Multiplikation scheint daher auch bei der NH +4 -Ausscheidung eine wesentliche Rolle zu spielen.
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Silbernagl, S., Scheller, D. Formation and excretion of NH3↔NH +4 . new aspects of an old problem. Klin Wochenschr 64, 862–870 (1986). https://doi.org/10.1007/BF01725559
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DOI: https://doi.org/10.1007/BF01725559