Mechanisms of Diabetic Renal Damage: Role of the Kinin Receptors

糖尿病肾损伤的机制：激肽受体的作用

• 批准号: 8127025
• 负责人: Parker C. Wilson
• 金额: $ 4.26万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2014-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127025
• 关键词: Affect; Affinity; Angiotensin II; Angiotensins; Arrestins; Behavior; Binding; Biological Models; Bioluminescence; Bradykinin; Bradykinin B1 Receptor; Bradykinin B2 Receptor; Bradykinin Receptor; Calcium; Calcium Signaling; Cell membrane; Cell model; Cells; Co-Immunoprecipitations; Complex; Coupled; Coupling; Cyclic AMP; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Dimerization; Disease; Energy Transfer; Exhibits; Extracellular Matrix; Family; GTP-Binding Proteins; Genes; Genetic; Genetic Transcription; Growth Factor; Heterodimerization; Injury; Insulin-Dependent Diabetes Mellitus; Kidney; Kinins; Laboratories; Ligands; Losartan; Measures; Mediating; Molecular; Molecular Conformation; Peptides; Population; Prevention; Property; Proteins; Rattus; Receptor Activation; Receptor Signaling; Relative (related person); Risk Factors; Role; Signal Transduction; Staging; Streptozocin; Testing; Tetracyclines; Up-Regulation; arrestin 2; base; connective tissue growth factor; diabetic; dimer; kidney cell; kidney vascular structure; mesangial cell; novel; novel therapeutic intervention; programs; protein activation; receptor; receptor expression; receptor internalization; response; trafficking

DESCRIPTION (provided by applicant): Bradykinin receptors (B1, B2) are GPCRs that have been implicated in the proliferative and fibrotic response that characterizes diabetic nephropathy. Bradykinin receptor expression is increased in the diabetic glomerulus, and their activation initiates transcription of the pro-fibrotic genes: CTGF and TGF2R1. Co-immunoprecipitation and fluorescent colocalization studies have shown that the B2 receptor forms heterodimers with the angiotensin 2 type 1 (AT1R) receptor on the plasma membrane. AT1-B2 heterodimer formation potentiates calcium signaling which may aggravate the fibrotic response. We hypothesize that elevated expression of the AT1R increases the population of AT1-B2 heterodimers, and promotes bradykinin- independent internalization of B2 receptors by SII[Sar1, Ile4, Ile8]-angiotensin (a peptide antagonist of the AT1R that causes 2-arrestin dependent internalization without coupling to G proteins) but not by losartan (a non-peptide neutral antagonist). In an AT1R tetracycline-inducible HEK cell model, SII pretreatment was a non- competitive antagonist of bradykinin-induced calcium signaling whereas losartan had no effect. Similar results were obtained in primary rat VSMCs. We hypothesize that AT1R antagonists that induce receptor internalization can function as allosteric antagonists of bradykinin signaling in conditions that favor the formation of heterodimers, suggesting their utility in the prevention of diabetic nephropathy progression. PUBLIC HEALTH RELEVANCE: Understanding how diabetes alters the behavior of kidney cells is essential to developing novel therapeutic approaches for the treatment of diabetic kidney disease. This proposal will investigate how receptor-receptor interaction affects cell signaling.

描述（由申请人提供）：缓激肽受体（B1、B2）是与糖尿病肾病特征的增殖和纤维化反应有关的GPCR。糖尿病肾小球中的缓激肽受体表达增加，它们的激活启动促纤维化基因：CTGF 和 TGF2R1 的转录。免疫共沉淀和荧光共定位研究表明，B2 受体与质膜上的血管紧张素 2 1 型 (AT1R) 受体形成异二聚体。 AT1-B2 异二聚体的形成增强了钙信号传导，可能会加剧纤维化反应。我们假设 AT1R 表达升高会增加 AT1-B2 异二聚体的数量，并通过 SII[Sar1、Ile4、Ile8]-血管紧张素（AT1R 的肽拮抗剂，导致 2-arrestin 依赖性）促进 B2 受体的缓激肽独立内化。内化而不与 G 蛋白偶联），但不是氯沙坦（一种非肽中性拮抗剂）。在 AT1R 四环素诱导的 HEK 细胞模型中，SII 预处理是缓激肽诱导的钙信号传导的非竞争性拮抗剂，而氯沙坦则没有效果。在原代大鼠 VSMC 中也获得了类似的结果。我们假设，诱导受体内化的 AT1R 拮抗剂可以在有利于异二聚体形成的条件下充当缓激肽信号传导的变构拮抗剂，这表明它们在预防糖尿病肾病进展方面的用途。 公共卫生相关性：了解糖尿病如何改变肾细胞的行为对于开发治疗糖尿病肾病的新治疗方法至关重要。该提案将研究受体-受体相互作用如何影响细胞信号传导。