Why is D-serine nephrotoxic and α-aminoisobutyric acid protective?
Why is D-serine nephrotoxic and α-aminoisobutyric acid protective?
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DOI：
10.1152/ajprenal.00441.2006
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发表时间：
2007-07-01
影响因子：
4.2
通讯作者：
Silbernagl, Stefan
中科院分区：
文献类型：
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作者：
Krug, Alexander W.;Voelker, Katharina;Silbernagl, Stefan
丝氨酸选择性地引起大鼠近端小管S-3段坏死。这导致氨基酸尿和糖尿。共同注射非代谢氨基酸α-氨基异丁酸（AIB）可预防肾小管病变。D-丝氨酸被S-3选择性重吸收，从而获得过氧化物酶体D-氨基酸氧化酶（D-AAO）。D-AAO介导的代谢产生活性氧。我们测定了D-丝氨酸单独或与还原型谷胱甘肽（GSH）或AIB一起腹腔注射后大鼠氨基酸和葡萄糖的排泄分数。两种化合物均预防高氨基酸尿症。我们在注射D-丝氨酸之前（对照组）和之后测量了肾组织中的GSH浓度，发现GSH水平下降至对照组的30%。当等摩尔GSH与D-丝氨酸共注射时，这种减少被阻止。为了找出AIB保护肾小管免受D-丝氨酸毒性的原因，我们在体内将D-[C-14]丝氨酸或[C-14] AIB（0.36 mmol/l）与[H-3]菊粉一起微注入晚期近端肾小管，并测量最终尿液中的放射性。D-[C-14]丝氨酸和[C-14] AIB的重吸收分数分别为55%和70%，80 mmol/l的AIB或D-丝氨酸在很大程度上相互阻止重吸收。体外测定的D-AAO活性（使用D-丝氨酸作为底物）不受10倍高的AIB浓度的影响。我们从这些结果得出结论：1）D-AAO介导的D-丝氨酸代谢降低肾GSH浓度，从而引起肾小管损伤，因为GSH减少了活性氧物质的减少，2）AIB通过抑制S3段中的D-丝氨酸摄取而不是通过干扰细胞内D-AAO介导的D-丝氨酸代谢来预防D-丝氨酸诱导的肾小管病变。
Serine selectively causes necrosis of S-3 segments of proximal tubules in rats. This leads to aminoaciduria and glucosuria. Coinjection of the nonmetabolizable amino acid alpha-aminoisobutyric acid (AIB) prevents the tubulopathy. D-serine is selectively reabsorbed in S-3, thereby gaining access to peroxisomal D-amino acid oxidase (D-AAO). D-AAO-mediated metabolism produces reactive oxygen species. We determined the fractional excretion of amino acids and glucose in rats after intraperitoneal injection of D-serine alone or together with reduced glutathione (GSH) or AIB. Both compounds prevented the hyperaminoaciduria. We measured GSH concentrations in renal tissue before (control) and after D-serine injection and found that GSH levels decreased to similar to 30% of control. This decrease was prevented when equimolar GSH was coinjected with D-serine. To find out why AIB protected the tubule from D-serine toxicity, we microinfused D-[C-14] serine or [C-14] AIB (0.36 mmol/l) together with [H-3] inulin in late proximal tubules in vivo and measured the radioactivity in the final urine. Fractional reabsorption of D-[C-14] serine and [C-14] AIB amounted to 55 and 70%, respectively, and 80 mmol/l of AIB or D-serine mutually prevented reabsorption to a great extent. D-AAO activity measured in vitro (using D- serine as substrate) was not influenced by a 10-fold higher AIB concentration. We conclude from these results that 1) D-AAO-mediated D-serine metabolism lowers renal GSH concentrations and thereby provokes tubular damage because reduction of reactive oxygen species by GSH is diminished and 2) AIB prevents D- serine-induced tubulopathy by inhibition of D-serine uptake in S3 segments rather than by interfering with intracellular D-AAO-mediated D-serine metabolism.