The role of carnosinase-1 and its mechanism in the progression of chronic kidney disease

肌肽酶1在慢性肾脏病进展中的作用及其机制

• 批准号: 392039634
• 负责人: Professorin Dr. Sigrid Hoffmann, Ph.D.
• 金额: --
• 依托单位: V. Medizinische Klinik: Nephrologie, Endokrinologie, Diabetologie, Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392039634?language=en
• 关键词: role; carnosinase; its; mechanism; progression

Carnosine is a natural dipeptide present in mammalian tissues and available as an over-the-counter food additive. In humans, beneficial effects of carnosine have been shown in clinical trials in exercise physiology, psychology, psychiatry, and recently in pre-diabetic overweight volunteers. Although the potential mechanisms of carnosine's action, i.e. lowering chronic low-grade inflammation, oxidative stress, advanced glycation, and lipidoxidation end products (AGEs and ALEs, respectively), on diabetic complications have been suggested, the role of carnosinase-1 (CN-1) in the progression of chronic kidney disease (CKD) is incompletely understood. In line with data from cross-sectional studies in patients with type 2 diabetes that muscle carnosine levels are decreased, the current cooperative project hypothesizes that an increased renal CN-1 expression will deplete renal HCD stores making renal tissue more prone to hyperglycemia mediated damage. The beneficial effect of carnosine supplementation in diabetic models is attributed to its tissue protective properties and in part to its hyperglycemia lowering propensity, ultimately leading to diminished hyperfiltration. Basal levels of CN-1 in serum and urine are genetically determined by the (CTG)n repeat polymorphism and possibly by SNPs within the CNDP1 gene. In normoalbuminuric CKD patients increased urinary CN-1 concentration may reflect increases in renal CN-1 expression and thus may be used as an early biomarker to assess patients at risk for renal function deterioration. By making use of animal models we will assess if the beneficial effect of carnosine is mediated via tubuloglomerular feedback and if carnosine is also protective in a non-diabetic model of glomerulosclerosis. These studies will be complemented with cross-sectional clinical studies to assess the relations between carnosinasuria, CNDP1 genotype and progression of CKD in diabetic and non-diabetic patients. Finally in vitro studies with cultured renal cells will be performed to assess the influence of CNDP1 over-expression.

肌肽是存在于哺乳动物组织中的天然二肽，并且可作为非处方食品添加剂获得。在人类中，肌肽的有益作用已在运动生理学、心理学、精神病学的临床试验中以及最近在糖尿病前期超重志愿者中显示。虽然肌肽作用的潜在机制，即降低慢性低度炎症、氧化应激、晚期糖基化和糖基化终产物（分别为AGEs和ALE）对糖尿病并发症的作用已被提出，但肌肽酶-1（CN-1）在慢性肾脏疾病（CKD）进展中的作用尚不完全清楚。 根据2型糖尿病患者的横断面研究数据，肌肉肌肽水平降低，目前的合作项目假设肾脏CN-1表达增加将耗尽肾脏HCD储存，使肾组织更容易发生高血糖介导的损伤。肌肽补充剂在糖尿病模型中的有益作用归因于其组织保护特性，部分归因于其降低高血糖倾向，最终导致超滤减少。血清和尿液中CN-1的基础水平由（CTG）n重复多态性遗传决定，并可能由CNDP 1基因内的SNP决定。在正常白蛋白尿的CKD患者中，尿CN-1浓度增加可能反映了肾脏CN-1表达的增加，因此可用作评估患者肾功能恶化风险的早期生物标志物。通过利用动物模型，我们将评估肌肽的有益作用是否通过肾小管肾小球反馈介导，以及肌肽是否在肾小球硬化的非糖尿病模型中也具有保护作用。这些研究将辅以横断面临床研究，以评估糖尿病和非糖尿病患者中肌肽尿、CNDP 1基因型与CKD进展之间的关系。最后，用培养的肾细胞进行体外研究以评估CNDP 1过表达的影响。