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Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-MNovelty and Significance
Circulation Research ( IF 20.1 ) Pub Date : 2018-02-16 , DOI: 10.1161/circresaha.117.312144
Jane A Mitchell 1 , Rebecca B Knowles 1 , Nicholas S Kirkby 1 , Daniel M Reed 1 , Matthew L Edin 1 , William E White 1 , Melissa V Chan 1 , Hilary Longhurst 1 , Magdi M Yaqoob 1 , Ginger L Milne 1 , Darryl C Zeldin 1 , Timothy D Warner 1
Affiliation  

Rationale: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A2, which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A2 are formed after the concerted actions of cPLA2α (cytosolic phospholipase A2) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2 formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney.
Objective: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA2α knockout, kidney-specific knockin. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2 in the circulation.
Methods and Results: Metabolites were measured using liquid chromatography-tandem mass spectrometry. Endothelial cells were grown from blood progenitors. Before kidney transplantation, the patient’s endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-keto-prostaglandin F) and thromboxane A2 (measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. After transplantation and the establishment of normal renal function, the levels of PGI-M and TX-M in the patient’s urine rose to within normal ranges, whereas endothelial production of prostacyclin and platelet production of thromboxane A2 remained negligible.
Conclusions: These data show that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A2 by platelets in the general circulation. Previous work relying on urinary metabolites of prostacyclin and thromboxane A2 as markers of whole-body endothelial and platelet function now requires reevaluation.


中文翻译:

缺乏细胞溶质磷脂酶 A2 的患者的肾移植证明了尿液 PGI-M 和 TX-M 的肾脏起源新奇和意义

基本原理:抗血栓形成的血管前列环素和促血栓形成的血小板血栓素 A 2之间的平衡是心血管健康的基础。前列环素和血栓素 A 2在 cPLA 2 α(胞质磷脂酶 A 2)和 COX(环氧合酶)的协同作用后形成。尿液中的 2,3-dinor-6-keto-PGF (PGI-M) 和 11-dehydro-TXB 2 (TX-M) 已被视为循环中前列环素和血栓素 A 2形成的生物标志物,并用于解释 COX尽管担心尿 PGI-M 和 TX-M 起源于肾脏,但生物学和患者表型。
目的:我们报告了一名携带极其罕见的 cPLA 2 α 基因突变的非凡患者的数据,导致前列环素和血栓素 A 2几乎完全丧失,该患者移植了正常肾脏,导致全身 cPLA 2 α敲除,肾脏特异性敲除。通过研究该患者,我们可以明确确定肾脏对 PGI-M 和 TX-M 产生的贡献,并测试它们作为循环中前列环素和血栓素 A 2标志物的有效性。
方法和结果:使用液相色谱-串联质谱法测量代谢物。内皮细胞由血液祖细胞生长。在肾移植之前,患者的内皮细胞和血小板释放的前列环素(以 6-酮基-前列腺素 F测量)和血栓素 A 2(以 TXB 2测量)的水平分别可忽略不计。同样,PGI-M 和 TX-M 的尿液水平也非常低。在移植和建立正常肾功能后,患者尿液中的 PGI-M 和 TX-M 水平上升至正常范围内,而内皮产生的前列环素和血小板产生的血栓素 A 2仍然可以忽略不计。
结论:这些数据表明,PGI-M 和 TX-M 可以仅来自肾脏,而不受内皮细胞产生的前列环素或全身循环中血小板产生的血栓素 A 2的贡献。以前依赖前列环素和血栓素 A 2的尿液代谢物作为全身内皮和血小板功能标志物的工作现在需要重新评估。
更新日期:2018-02-16
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