Renal endothelium and the development of chronic kidney disease in sickle cell disorders

镰状细胞病中的肾内皮和慢性肾病的发展

基本信息

  • 批准号:
    10659575
  • 负责人:
  • 金额:
    $ 65.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-15 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD), widespread among individuals with sickle cell disease (SCD), is a significant contributor to morbidity and early mortality. The progressive deterioration of renal health in SCD is associated with chronic intravascular hemolysis. However, the mechanistic approach to interpreting the hemolysis-driven pathogenesis of CKD in SCD is limited and therefore targeted therapies based on mechanistic models are lacking. Progressive loss of renal function, represented by increased albuminuria and reduced glomerular filtration rate (GFR), is associated with microvascular congestion in humans and mice with SCD. We postulated that circulating cell-free heme, a product of hemolysis, may instigate persistent endothelial damage that ensues CKD development. Endothelial protein C receptor (EPCR) maintains endothelial barrier integrity. We discovered an age-dependent as well as heme-induced loss of EPCR from renal microvascular endothelium in SCD (SS) mice. Concomitantly, the cleaved soluble form of EPCR (sEPCR) was elevated in the plasma associated with albuminuria. Using super-resolution ultrasound imaging, we found that younger SS mice challenged with the repetitive infusion of minimal doses of heme and the older SS mice without heme challenge incur substantial renal microvascular rarefaction. Heme induces endothelial P-selectin that promotes vascular congestion. Our pilot data show that reduced EPCR expression is associated with increased P-selectin on renal microvascular endothelium in the SS mice. Proteinase 3 (PR3), expressed on neutrophils, can degrade EPCR. In our repeated heme-challenged younger SS mice compared to vehicle-injected mice, we noticed increased expression of PR3 in plasma as well as in accumulated neutrophils from the kidneys. Moreover, we found that heme induces acetylation of histone 4 Lys 16 residues (H4K16ac) which are known to promote the biosynthesis of PR3. Based on these preliminary data, we hypothesize that heme-induced P-selectin and PR3 concurrently result in the loss of EPCR leading to endothelial disintegration, microvascular congestion, and CKD development in SCD. We will test this hypothesis with three specific aims that integrate experiments with human renal endothelial cells and neutrophils in vitro, murine models, and clinical samples from multiple cohorts of SCD patients. Aim 1 will determine that repeated low-dose heme insults promote renal endothelial P-selectin that suppresses EPCR leading to vascular damage and development of CKD in mice with SCD. Aim 2 will test whether heme- activated PR3 facilitates EPCR cleavage and expedite CKD in SCD. Aim 3 will determine whether sEPCR and specific genetic variants of EPCR can indicate the risk of CKD in SCD patients.
项目总结/摘要 慢性肾脏病(CKD),广泛存在于镰状细胞病(SCD)患者中,是一种重要的肾脏疾病。 导致发病和早期死亡。SCD患者肾脏健康的进行性恶化与 慢性血管内溶血然而,解释溶血驱动的 CKD在SCD中的发病机制是有限的,因此基于机制模型的靶向治疗是 缺乏肾功能进行性丧失,表现为白蛋白尿增加和肾小球减少 滤过率(GFR)与患有SCD的人和小鼠的微血管充血有关。我们假设 循环中的无细胞血红素,一种溶血产物,可能引起持续的内皮损伤, CKD发展。内皮蛋白C受体(EPCR)维持内皮屏障的完整性。我们发现 SCD(SS)中肾脏微血管内皮EPCR的年龄依赖性和血红素诱导的丧失 小鼠与此同时,血浆中裂解的可溶性EPCR(sEPCR)升高, 蛋白尿使用超分辨率超声成像,我们发现年轻的SS小鼠受到 重复输注最低剂量的血红素和未进行血红素激发的老年SS小鼠会导致大量 肾微血管稀疏。血红素诱导内皮P-选择素,促进血管充血。我们 初步数据显示,EPCR表达减少与肾微血管上P-选择素增加有关。 SS小鼠的内皮细胞。蛋白酶3(PR 3),表达于中性粒细胞,可以降解EPCR。在我们反复的 与注射载体的小鼠相比,血红素激发的年轻SS小鼠,我们注意到PR 3的表达增加 血浆中以及肾脏中积聚的嗜中性粒细胞中。此外,我们发现,血红素诱导 组蛋白4Lys 16残基(H4 K16 ac)的乙酰化,已知其促进PR 3的生物合成。基于 根据这些初步数据,我们假设血红素诱导的P-选择素和PR 3同时导致了 EPCR导致SCD中的内皮崩解、微血管充血和CKD发展。我们将 用三个特定的目标来检验这一假设,这些目标是用人肾内皮细胞进行的实验, 体外嗜中性粒细胞、鼠模型和来自SCD患者的多个群组的临床样品。 目的1将确定反复低剂量血红素损伤促进肾内皮P-选择素,抑制肾内皮P-选择素的表达。 EPCR导致SCD小鼠的血管损伤和CKD发展。目标2将测试血红素- 活化的PR 3促进EPCR切割并加速SCD中的CKD。目标3将确定sEPCR和 EPCR的特异性遗传变异可以指示SCD患者中CKD的风险。

项目成果

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Samit Ghosh其他文献

Samit Ghosh的其他文献

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{{ truncateString('Samit Ghosh', 18)}}的其他基金

Molecular and Cellular Pathogenesis of Kidney Disease in Sickle Cell Disorders
镰状细胞病肾病的分子和细胞发病机制
  • 批准号:
    10542842
  • 财政年份:
    2021
  • 资助金额:
    $ 65.15万
  • 项目类别:
Molecular and Cellular Pathogenesis of Kidney Disease in Sickle Cell Disorders
镰状细胞病肾病的分子和细胞发病机制
  • 批准号:
    10117308
  • 财政年份:
    2021
  • 资助金额:
    $ 65.15万
  • 项目类别:
Molecular and Cellular Pathogenesis of Kidney Disease in Sickle Cell Disorders
镰状细胞病肾病的分子和细胞发病机制
  • 批准号:
    10318643
  • 财政年份:
    2021
  • 资助金额:
    $ 65.15万
  • 项目类别:

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