PDF(Pubmed)
Abstract：
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by epithelial proliferation and progressive cyst enlargement. Using a non-targeted high-resolution metabolomics approach, we analyzed biofluids from 36 ADPKD and 18 healthy controls with estimated glomerular filtration rate (eGFR) > 60 ml/min to identify features specific to ADPKD or that associate with disease severity [eGFR or height-corrected total kidney volume (htTKV)]. Multiple pathways differed between ADPKD subjects and controls, with the histidine pathway being the most highly represented. Plasma histidine, urinary N-methylhistamine, methylimidazole-acetaldehyde, and imidazole-acetaldehyde, as well as 3-methylhistidine and anserine were increased, while plasma N-acetylhistamine and urinary imidazole-acetic acid were decreased in ADPKD compared to controls. In ADPKD, urinary histidine and a histidine derivative, urocanate (a precursor of glutamate), were significantly associated. HtTKV and eGFR were inversely associated with urinary glutamine and plasma 4-imidazolone-5-propionic acid, respectively. Supernatant from cultured human ADPKD renal cystic epithelia demonstrated increased aspartate and glutamate levels at 8 and 24 hours compared to primary tubular epithelia (p < 0.001). Following exposure over 48 hours to α-fluromethylhistidine, an inhibitor of histamine production, primary human PKD1 cyst epithelia proliferation increased significantly from baseline (p < 0.01) and greater than non-cystic epithelia (p < 0.05). The histidine ammonia lyase inhibitor nitromethane reversed α-fluromethylhistidine-induced cyst epithelia proliferation indicating a role for glutamate in cyst growth. In conclusion, histidine metabolism is altered preferentially leading to glutamate production and epithelial proliferation in ADPKD and associates with disease severity.
摘要：
常染色体显性遗传性多囊肾病（ADPKD）的特征是上皮增生和进行性囊肿增大。使用非靶向高分辨率代谢组学方法，我们分析了36例ADPKD和18例肾小球滤过率(eGFR)>60ml/min的健康对照者的生物体液,以确定ADPKD特有的特征或与疾病严重程度相关的特征[eGFR或身高校正后的总肾脏体积(htTKV)].ADPKD受试者和对照组之间的多种途径不同，组氨酸途径的代表性最高。血浆组氨酸，尿N-甲基组胺，甲基咪唑-乙醛，和咪唑-乙醛，以及3-甲基组氨酸和山丝氨酸增加，与对照组相比，ADPKD的血浆N-乙酰组胺和尿咪唑乙酸降低。在ADPKD中，尿组氨酸和组氨酸衍生物，尿糖酸（谷氨酸的前体），显著相关。HtTKV和eGFR与尿谷氨酰胺和血浆4-咪唑酮-5-丙酸呈负相关，分别。来自培养的人ADPKD肾囊性上皮的上清液显示与原发性肾小管上皮相比在8小时和24小时增加的天冬氨酸和谷氨酸水平(p<0.001)。暴露于α-氟甲基组氨酸超过48小时后，组胺产生的抑制剂,原发性人PKD1囊肿上皮增殖较基线显著增加(p<0.01),且高于非囊性上皮(p<0.05)。组氨酸氨裂解酶抑制剂硝基甲烷逆转了α-氟甲基组氨酸诱导的囊肿上皮增殖，表明谷氨酸在囊肿生长中的作用。总之,在ADPKD中,组氨酸代谢优先改变,导致谷氨酸生成和上皮增殖,并与疾病严重程度相关。
