TRPC channels in proteinuric kidney disease

TRPC 通道在蛋白尿肾病中的作用

• 批准号: 8245833
• 负责人: Anna Greka
• 金额: $ 15.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245833
• 关键词: Adhesions; Affect; Angiotensin II; Angiotensins; Animal Model; Animals; Architecture; Area; Biological Assay; Calcium; Cell membrane; Cell physiology; Data; Development; Diabetic Nephropathy; Disease; Employee Strikes; Ensure; Epidermal Growth Factor Receptor; Focal Segmental Glomerulosclerosis; Foot Process; Gadolinium; Genes; Genetic; Health; Image; Injury; Intracellular translocation; Ion Channel; Kidney Diseases; Kidney Failure; Knock-out; Measurable; Mediating; Membrane; Membrane Protein Traffic; Modeling; Molecular; Mutation; Nephrosis; Nephrotic Syndrome; Patch-Clamp Techniques; Pathway interactions; Patients; Pharmaceutical Preparations; Process; Property; Proteinuria; Receptor Protein-Tyrosine Kinases; Receptor, Angiotensin, Type 1; Regulation; Regulatory Pathway; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Techniques; Testing; Time; Transactivation; Transgenic Organisms; Work; base; gadolinium oxide; gain of function mutation; migration; novel; patch clamp; podocyte; prevent; receptor; research study; response; slit diaphragm; src-Family Kinases; trafficking; wound

DESCRIPTION (provided by applicant): The canonical transient receptor potential channel 6 (TRPC6) has been recently added to the growing number of genes involved in familial forms of proteinuric kidney disease, characterized by nephrosis and ultimate renal failure. Interestingly, all TRPC6 mutations known to date are gain of function mutations, suggesting that increased Ca+2 influx through TRPC6 channels leads to podocyte injury. The mechanisms for TRPC channel regulation in podocytes are largely unknown. Furthermore, the question remains whether an increase in Ca+2 influx through TRPC channels occurs in both genetic and acquired forms of proteinuric kidney disease. Our preliminary data suggest that TRPC1 and TRPC5 are expressed in glomerular podocytes, where, like TRPC6, they localize to podocyte foot processes, in the vicinity of slit diaphragms. Our adhesion assays and wound assays in podocytes demonstrate a striking translocation of channel to membrane ruffles, indicating that channel localization is a regulated process. Angiotensin induces prominent calcium transients in podocytes expressing the AT1R, and a significant portion of this calcium influx appears to be mediated by TRPC channels. Patch clamp experiments in podocytes confirm the presence of a TRPC-like current. Single channel recordings suggest that channel activity is regulated by channel translocation to the membrane. When membrane trafficking is disrupted by pharmacologic and molecular techniques in podocytes, the TRPC-like current is largely diminished, supporting the notion that channel activity is regulated by channel translocation to the membrane. Based on our preliminary work, we hypothesize that TRPC1 and TRPC5 form novel channels in podocytes, which, in concert with TRPC6, mediate Ca+2 influx by their regulated translocation to the plasma membrane in response to upstream signaling through the Angiotensin Type 1 Receptor. PUBLIC HEALTH RELEVANCE: This work on the role of TRPC channels in proteinuric kidney disease will help identify targets for the development of medications and therapies to treat and prevent diseases such as nephrotic syndrome and diabetic nephropathy, which currently affect many kidney disease patients worldwide.

描述（由申请人提供）：最近添加了典型的瞬态受体电势通道（TRPC6），添加到涉及蛋白尿肾脏疾病的家族形式的基因数量中，其特征是肾脏症和最终的肾衰竭。有趣的是，迄今已知已知的所有TRPC6突变都是功能突变的增益，这表明通过TRPC6通道增加CA+2涌入会导致足细胞损伤。足细胞中TRPC通道调节的机制在很大程度上未知。此外，问题仍然是，在遗传和获得形式的蛋白尿肾脏疾病中，通过TRPC通道的Ca+2涌入是否增加。我们的初步数据表明，TRPC1和TRPC5在肾小球足细胞中表达，其中像TRPC6一样，它们本地化为足细胞脚的过程，在Slit diaphragms附近。我们在足细胞中的粘附测定和伤口分析表明，通道向膜荷叶边的易位易位，表明通道定位是一个受调节的过程。血管紧张素在表达AT1R的足细胞中诱导显着的钙瞬变，并且该钙涌入的很大一部分似乎是由TRPC通道介导的。足细胞中的斑块夹实验证实了TRPC样电流的存在。单个通道记录表明，通道活动是通过通道易位到膜调节的。当膜运输被足细胞中的药物和分子技术破坏时，类似TRPC的电流在很大程度上会大大减少，这支持了通道活性受通道转移到膜的调节的观点。基于我们的初步工作，我们假设TRPC1和TRPC5在足细胞中形成了新通道，与TRPC6一起，通过调节的易位，通过TRPC6介导CA+2涌入质膜，响应于血管素1型受体的上游信号，以响应上游信号。 公共卫生相关性：这项关于TRPC通道在蛋白尿肾脏疾病中的作用的工作将有助于确定针对治疗和预防疾病（例如肾病综合征和糖尿病性肾病）的药物和疗法的靶标，目前影响了全球许多肾脏病患者。