Karet F E, Davenport A P
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, UK.
Nephrol Dial Transplant. 1996 Oct;11(10):1976-82. doi: 10.1093/oxfordjournals.ndt.a027084.
Despite intensive investigation, a pathophysiological role for the endogenous vasoconstrictor peptide endothelin (ET) remains elusive. The kidney is particularly sensitive to the effects of ET, which are mimicked by the administration of cyclosporin A (CsA), and animal models suggest a role for ET in the vasoconstrictive effects of CsA. Using a recently validated novel fluorescent quantitative RT-PCR assay to enable the direct study of human renal biopsies, we have quantified mRNA for the two known ET receptor subtypes ETA and ETB in cortical tissue from three groups of patients: renal transplant recipients on CsA (n = 7), those with native renal disease (n = 5) and normal controls (n = 7). Median and mRNA levels (amol/microgram total RNA) were 0.024, 0.17 and 0.2 respectively for ETA and 0.57, 0.64 and 0.96 for ETB. These values indicate significant downregulation of ETA (P = 0.003) but not ETB (P = 0.104) mRNA in the transplant group. These results provide the first demonstration of a perturbation in the human ET system at tissue level in a pathophysiological situation, and suggest that the deleterious renal vasoconstrictor effects of CsA might be ameliorated by selective ETA receptor antagonism in the future. This study also illustrates the feasibility of ex vivo analysis of human diagnostic material at the molecular level.
尽管进行了深入研究，内源性血管收缩肽内皮素（ET）的病理生理作用仍不清楚。肾脏对ET的作用特别敏感，环孢素A（CsA）的给药可模拟这些作用，动物模型表明ET在CsA的血管收缩作用中起作用。我们使用最近验证的新型荧光定量逆转录-聚合酶链反应（RT-PCR）测定法直接研究人类肾活检组织，对三组患者皮质组织中两种已知的ET受体亚型ETA和ETB的mRNA进行了定量：接受CsA治疗的肾移植受者（n = 7）、患有原发性肾脏疾病的患者（n = 5）和正常对照者（n = 7）。ETA的mRNA水平（amol/微克总RNA）中位数分别为0.024、0.17和0.2，ETB的分别为0.57、0.64和0.96。这些值表明移植组中ETA mRNA有显著下调（P = 0.003），而ETB mRNA无显著下调（P = 0.104）。这些结果首次证明了在病理生理情况下人类ET系统在组织水平上的紊乱，并表明未来通过选择性ETA受体拮抗作用可能改善CsA有害的肾血管收缩作用。这项研究还说明了在分子水平上对人类诊断材料进行离体分析的可行性。
