Döring Frank, Schmitt Roland, Bernhardt Wanja M, Klapper Maja, Bachmann Sebastian, Daniel Hannelore, Groneberg David A
Otto-Heubner-Center, Biomedical Research Center, Charité - Medical School of the Free University and Humboldt-University, D-13353 Berlin, Germany.
Biol Chem. 2005 Aug;386(8):785-90. doi: 10.1515/BC.2005.092.
The kidney is a target organ for thyroid hormone action and a variety of renal transport processes are altered in response to impaired thyroid functions. To investigate the effect of thyroid hormone on the expression of the renal proximal tubular high-affinity-type H(+)-peptide cotransporter (PEPT2) in rats, hypothyroidism was induced in animals by administration of methimazole (0.05%) via drinking water. After 7 weeks of treatment, hypothyroidism was confirmed by determining serum free T(3) and free T(4) concentrations. Northern blotting was used to examine the expression of PEPT2 mRNA in kidney tissues from hypothyroid rats compared to control rats. Hypothyroidism resulted in an increased level of total renal PEPT2 mRNA (121.1+/-3.3% vs. control 100+/-2.8%; p=0.008). The mRNA results were confirmed by immuno-blotting, which demonstrated significantly increased protein levels (162% vs. control 100%; p<0.01). Immunohistochemistry also revealed increased PEPT2 protein levels in the proximal tubules of treated compared to non-treated rats. In summary, PEPT2 is the first proximal tubule transporter protein that shows increased expression in states of hypothyreosis. As PEPT2 reabsorbs filtered di- and tripeptides and peptide-like drugs, the present findings may have important implications in nutritional amino acid homeostasis and for drug dynamics in states of altered thyroid function.
肾脏是甲状腺激素作用的靶器官，甲状腺功能受损时，各种肾脏转运过程会发生改变。为了研究甲状腺激素对大鼠肾近端小管高亲和力型H(+)-肽共转运体（PEPT2）表达的影响，通过饮水给予甲巯咪唑（0.05%）诱导动物发生甲状腺功能减退。治疗7周后，通过测定血清游离T(3)和游离T(4)浓度确认甲状腺功能减退。与对照大鼠相比，采用Northern印迹法检测甲状腺功能减退大鼠肾组织中PEPT2 mRNA的表达。甲状腺功能减退导致肾脏总PEPT2 mRNA水平升高（121.1±3.3%对对照100±2.8%；p = 0.008）。免疫印迹法证实了mRNA结果，该方法显示蛋白水平显著升高（162%对对照100%；p<0.01）。免疫组织化学也显示，与未治疗大鼠相比，治疗大鼠近端小管中PEPT2蛋白水平升高。总之，PEPT2是首个在甲状腺功能减退状态下表达增加的近端小管转运蛋白。由于PEPT2重吸收滤过的二肽和三肽以及类肽药物，本研究结果可能对营养性氨基酸稳态以及甲状腺功能改变状态下的药物动力学具有重要意义。
