Dahlmann A, Dantzler W H, Silbernagl S, Gekle M
Physiologisches Institut, Universität Würzburg, Germany.
J Pharmacol Exp Ther. 1998 Jul;286(1):157-62.
Ochratoxin A (OTA) is a widespread nephrotoxin excreted to a substantial degree via the kidney. Previously we showed that [3H]OTA can be reabsorbed along the rat nephron in vivo (Zingerle et al., 1997). In this study we investigated in detail the contribution of different nephron segments to [3H]OTA reabsorption and determined the possible mechanisms involved by microinfusion and microperfusion experiments. At pH 6 (approximately 94% of OTA neutral), OTA is reabsorbed in all nephron segments investigated. The estimated fractional reabsorptions (FR) at a tubular load of 20 fmol/min are: proximal convoluted tubule (PCT), 14.8%; proximal straight tubule (PST), 27.4%; ascending limb of Henle's loop (ALH), 13.6%; distal tubule (DT), 11.6%; collecting duct (CD), 24.6%; terminal CD, 22.0%. At pH 8 (approximately 10% of OTA neutral) FR are as follows: PCT, 0%; PST, 25.9%; ALH, 14.0%; DT, 3.2%; CD, 8.2%. Thus, OTA reabsorption in PST and ALH in pH-independent. Reabsorption in PST but not in DT or CD was inhibited by sulfobromophthalein, a substrate of the apical organic anion carrier. L-Phenylalanine did not reduce OTA reabsorption. After intravenous injection of unlabeled OTA, resulting in a plasma concentration of approximately 10(-5) mol/l, the FR of [3H]OTA during early proximal microinfusion was reduced slightly. From our results we conclude: 1) OTA can be reabsorbed in all nephron segments investigated. 2) Under physiological conditions the predominant sites of reabsorption are PST, ALH and terminal CD. 3) Reabsorption in PST and ALH is not pH-dependent. 4) pH-independent reabsorption in PST is mediated by the apical organic anion transporter (OAT-K1), whereas pH-dependent reabsorption in PCT is mediated by H(+)-dipeptide cotransporter(s). 5) Reabsorption also takes place during natural exposure, i.e., when OTA is present in plasma and renal tissue. 6) The high FR in ALH and CD explains, at least in part, the preferential impairment of postproximal functions and the accumulation in renal inner medulla and papila.
赭曲霉毒素A（OTA）是一种广泛存在的肾毒素，很大程度上通过肾脏排泄。此前我们发现，[3H]OTA在体内可沿大鼠肾单位被重吸收（津格勒等人，1997年）。在本研究中，我们详细研究了不同肾单位节段对[3H]OTA重吸收的贡献，并通过微量注射和微量灌注实验确定了其中可能涉及的机制。在pH值为6（约94%的OTA呈中性）时，OTA在所研究的所有肾单位节段中均被重吸收。在肾小管负荷为20飞摩尔/分钟时，估计的重吸收分数（FR）分别为：近端曲管（PCT），14.8%；近端直小管（PST），27.4%；髓袢升支粗段（ALH），13.6%；远曲小管（DT），11.6%；集合管（CD），24.6%；终末集合管，22.0%。在pH值为8（约10%的OTA呈中性）时，FR如下：PCT，0%；PST，25.9%；ALH，14.0%；DT，3.2%；CD，8.2%。因此，PST和ALH中OTA的重吸收与pH无关。PST中的重吸收，但DT或CD中则不然，被磺溴酞钠抑制，磺溴酞钠是顶端有机阴离子载体的底物。L-苯丙氨酸并未降低OTA的重吸收。静脉注射未标记的OTA后，血浆浓度约为10^(-5)摩尔/升，早期近端微量注射期间[3H]OTA的FR略有降低。根据我们的结果，我们得出以下结论：1）OTA可在所研究的所有肾单位节段中被重吸收。2）在生理条件下，重吸收的主要部位是PST、ALH和终末集合管。3）PST和ALH中的重吸收不依赖于pH。4）PST中不依赖pH的重吸收由顶端有机阴离子转运体（OAT-K1）介导，而PCT中依赖pH的重吸收由H(+) - 二肽共转运体介导。5）在自然暴露期间，即当OTA存在于血浆和肾组织中时，也会发生重吸收。6）ALH和CD中的高FR至少部分解释了近端后功能的优先受损以及肾内髓质和乳头中的蓄积。
