Proton pump inhibitor-induced risk of chronic kidney disease is associated with increase of indoxyl sulfate synthesis via inhibition of CYP2E1 protein degradation
Proton pump inhibitor-induced risk of chronic kidney disease is associated with increase of indoxyl sulfate synthesis via inhibition of CYP2E1 protein degradation
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质子泵抑制剂诱发的慢性肾病风险与通过抑制 CYP2E1 蛋白降解增加硫酸吲哚酚合成有关
DOI：
10.1016/j.cbi.2022.110219
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发表时间：
2022-10-17
影响因子：
5.1
通讯作者：
Zhou, Hui
中科院分区：
文献类型：
--
作者：
Lu, Shuanghui;Zhao, Jieping;Zhou, Hui
质子泵抑制剂（PPI）被广泛用于治疗胃肠道酸相关疾病;然而，PPI的使用通过不明确的机制增加了慢性肾脏疾病（CKD）的风险。考虑到PPI干扰肠道微生物组平衡，这参与了肠源性尿毒症毒素蓄积的前体，并且肠源性尿毒症毒素加重了CKD进展，本研究的目的是阐明PPI是否影响肠源性尿毒症毒素代谢，包括硫酸吲哚酚（IS）、对甲苯基硫酸酯和三甲胺-N-氧化物，作为导致CKD的机制。本研究表明，PPI（奥美拉唑、兰索拉唑和泮托拉唑，30 mg/kg）在小鼠中给药3周仅增加了上述3种肠源性尿毒症毒素的IS血浆水平。此外，兰索拉唑随着暴露剂量（7.5-30 mg/kg）和持续时间（1-3周）的增加，IS血浆浓度沿着升高。然而，仅在暴露于PPI（30 mg/kg）治疗3周的组中观察到肾毒性伴肾小球结构轻度变化和纤维化体征。由于结肠中吲哚（肠道代谢的IS前体）浓度仅在泮托拉唑治疗组中增加，因此IS暴露增加的机制仍不清楚。进一步研究表明，PPI（奥美拉唑和兰索拉唑;但不是泮托拉唑）以浓度依赖性方式增加了原代小鼠肝细胞中吲哚的IS生成。此外，由于降解受到抑制，肝脏CYP 2 E1（介导IS形成的关键酶）的蛋白水平升高，导致IS水平升高。尽管奥美拉唑和兰索拉唑在体外可显著抑制hOAT 1/3的IS摄取，但PPI治疗3周并未减少小鼠的IS肾脏排泄。总之，PPI通过增加肝脏CYP 2 E1蛋白水平诱导IS合成，随后导致IS暴露量增加。这些发现提供了一种合理的生物学机制来解释PPI使用与CKD风险增加的相关性。
Proton pump inhibitors (PPIs) are widely used to treat acid-related disorders in the gastrointestinal tract; however, PPI use increases the risk of chronic kidney disease (CKD) through unclear mechanisms. Considering that PPIs disturb the gut microbiome balance, which is involved in the precursor of gut-derived uremic toxin accumulation, and that gut-derived uremic toxins aggravate CKD progression, the aim of this study is to elucidate whether PPIs affect gut-derived uremic toxin metabolism, including indoxyl sulfate (IS), p-cresyl sulfate, and trimethylamine-N-oxide, as a mechanism for causing CKD. The present study showed that 3 week-treatment of PPIs (omeprazole, lansoprazole, and pantoprazole at 30 mg/kg) in mice only increased IS plasma levels among the above three gut-derived uremic toxins. Additionally, lansoprazole increased IS plasma concentrations along with increased exposure dose (7.5-30 mg/kg) and duration (1-3 weeks). However, nephrotoxicity with mild changes in glomerular structure and signs of fibrosis were observed only in groups exposed to a 3-week treatment of PPIs (30 mg/kg). As the concentrations of indole (the precursor of IS from gut metabolism) in the colon were only increased in the pantoprazole-treated group, the mechanism of increased IS exposure remains unclear. Further studies revealed that PPIs (omeprazole and lansoprazole; but not pantoprazole) increased IS production from indole in primary mouse hepatocytes in a concentration-dependent manner. Additionally, the increased protein levels of hepatic CYP2E1 (the key enzyme mediating IS formation) due to suppressed degradation resulted in an increase in IS levels. Although omeprazole and lansoprazole significantly inhibited IS uptake in hOAT1/3 in vitro, 3 weeks of PPI treatment did not reduce IS renal excretion in mice. In conclusion, PPIs induced IS synthesis via increased hepatic CYP2E1 protein level, subsequently leading to increased IS exposure. These findings present a plausible biological mechanism to explain the association of PPI use with the increased risk of CKD.