Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsstrasse 17, 91054 Erlangen, Germany.
Department of Chemistry and Pharmacy, Food Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Nikolaus-Fiebiger-Strasse 10, 91058 Erlangen, Germany.
J Biol Chem. 2020 May 8;295(19):6330-6343. doi: 10.1074/jbc.RA120.012890. Epub 2020 Mar 20.
The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene-Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.
糖尿病或尿毒症患者以及接受腹膜透析治疗的患者的血浆中，葡萄糖衍生的二羰基代谢物如甲基乙二醛 (MGO)、乙二醛 (GO) 和 3-脱氧葡萄糖酮 (3-DG) 的水平升高。升高的二羰基水平可能导致疼痛性神经病变的发展。在这里，我们使用刺激免疫反应性降钙素基因相关肽 (iCGRP) 释放作为伤害感受器激活的测量指标，发现每种二羰基代谢物都会诱导浓度依赖性、TRPA1 依赖性和 Ca 依赖性 iCGRP 释放。MGO、GO 和 3-DG 在毫摩尔范围内的作用大致相同。我们假设另一种二羰基化合物 3,4-二脱氧葡萄糖-3-烯 (3,4-DGE)，在热灭菌后存在于腹膜透析 (PD) 溶液中，会激活伤害感受器。我们还表明，在体温下，3,4-DGE 是由 3-DG 形成的，而在微摩尔范围内的 3,4-DGE 浓度有效地从分离的鼠皮诱导 iCGRP 释放。在分离的壁层腹膜 PD 液或单独的 3,4-DGE 的新型制剂中，在 PD 溶液中发现的浓度下，刺激 iCGRP 释放。我们还测试了炎症组织条件是否与二羰基化合物协同作用，从分离的皮肤中诱导 iCGRP 释放。MGO 与缓激肽或前列腺素 E 一起应用会导致 iCGRP 释放的相加效应，而 MGO 在 pH 值为 5.2 时的应用会导致释放减少，这可能是由于 MGO 介导的瞬时受体电位 (TRP) V1 受体抑制所致。这些结果表明，几种反应性二羰基化合物激活伤害感受器并增强炎症介质。我们的研究结果强调了二羰基化合物和 TRPA1 受体在糖尿病或肾脏疾病期间引起疼痛的作用。
