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Cellular mechanisms of hormone and drug interaction in ion transport in the nephron

肾单位离子转运中激素和药物相互作用的细胞机制

基本信息

批准号：
12470022
负责人：
IMAI Masashi
金额：
$ 4.48万
依托单位：
JICHI MEDICAL SCHOOL
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470022/
关键词：
HCO_3 transport proximal straight tubule troglitazone PGE2 PGE2-knockout mice P-glycoprotein P-glycoprotein-knockout mice in vitro microperfusion インスリン CS-045 近位尿細管 Na-HCO3共輸送 PGE2受容体 Na利尿浮腫

项目摘要

(1) Function of P-glycoprotein in the proximal tubuleTo clarify the functional significance of the P-gp in the proximal tubule, we perfused proximal straight tubule (PST) isolated from the control and the P-gp knockout mice (mdr1a/ab(-)(-)). The activity of the transporter was assessed by microfluorometry of rodamine uptake to the kidney epithelia. In the control animals, T1/2 of the rotamine uptake was 34 sec, and verapamil, a blocker of P-gp, increased the value to 434 sec. By contrast, in the KO mice, T1/2 was 407 sec without any treatments, and it was unchanged after verapamil. Repeated administration of digoxin to the KO mice caused to increase the concentration of the drug in the kidney tissue. Subsequent studies using a proteinkinase C (PKC) stimulant (PMA), PKC inhibitors (staurosporine, H-7), and PI3-kinase inhibitors (wortomannin, LY294002) revealed that the function of P-gp is mediated by processes requiring both PKC and PI3-kinase.(2) Transition from avian to mammalian-type urine concentrating mechanisms during perinatal periodTo study functional significance of anatomical changes in the ascending limb from thick segment to thin segment by apoptosis during perinel period, we perfused isotaled medullary nephron segments obtained from varying perinatal periods. Active transport in the medullary thick ascending lim observed in the fetal period rapidly changed to Cl selective passive transport observed in the adult type thin ascending limb. While urea transporter in the inner medullary collecting duct is lacking during fetal period, the vasopressin sensitive transporter becomes apparent soon after the birth. It is concluded that transition from avian to mammalia type kidney is essential for attaining high urine concentration.

(1)近曲小管中P-糖蛋白的功能为了阐明近曲小管中P-gp的功能意义，我们对从对照和P-gp敲除小鼠(mdr1a/ab(-)(-))分离的近曲直管(PST)进行灌注。通过肾上皮细胞摄取罗明的显微荧光测定法评估转运蛋白的活性。在对照动物中，罗胺摄取的T1/2为34秒，而P-gp阻滞剂维拉帕米将该值增加至434秒。相比之下，在 KO 小鼠中，未经任何治疗，T1/2 为 407 秒，维拉帕米后则没有变化。对 KO 小鼠重复给予地高辛导致肾组织中药物浓度增加。随后使用蛋白激酶 C (PKC) 刺激剂 (PMA)、PKC 抑制剂（十字孢菌素，H-7）和 PI3 激酶抑制剂（沃托曼宁，LY294002）进行的研究表明，P-gp 的功能是由需要 PKC 和 PI3 激酶的过程介导的。(2) 从禽类尿液向哺乳动物型尿液的转变围产期的集中机制为了研究会阴期细胞凋亡导致升肢从粗段到细段的解剖学变化的功能意义，我们灌注了从不同围产期获得的等距髓质肾单位段。胎儿期观察到的髓质粗升肢的主动转运迅速转变为成人型细升肢中观察到的Cl选择性被动转运。虽然内髓集合管中的尿素转运蛋白在胎儿期缺乏，但加压素敏感转运蛋白在出生后不久就变得明显。结论是，从禽类肾向哺乳动物型肾的转变对于获得高尿液浓度至关重要。