Vascular Mechanisms of Hypertensive Nephropathy

高血压肾病的血管机制

• 批准号: 10533780
• 负责人: PAUL W. SANDERS
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533780
• 关键词: Adult; Albuminuria; Angiotensin II; Animal Model; Attention; Behavior; Birds; Blood Pressure Monitors; Blood Vessels; CCL2 gene; Cell Differentiation process; Chronic Kidney Failure; Dahl Hypertensive Rats; Defect; Development; End stage renal failure; Endothelial Cells; Event; Extracellular Matrix; Family; Fibrosis; Functional disorder; Gelatinase B; General Population; Glomerular Filtration Rate; Homeostasis; Homologous Gene; Human; Hypertension; Hypoxia; Impairment; Inflammation; Inflammatory; Injury; Investigation; Kidney; Kidney Diseases; Kidney Transplantation; Ligands; Macrophage; Mediating; Modeling; Molecular; Mutation; Oncogenes; Pathogenesis; Patients; Perivascular Fibrosis; Play; Population; Predisposition; Prevalence; Process; Production; Publishing; Rattus; Renal Hypertension; Renal function; Role; Series; Smooth Muscle; Smooth Muscle Myocytes; Telemetry; Time; Tissues; Vascular Smooth Muscle; Vascular remodeling; Veterans; Virus; arteriole; blood pressure elevation; cell growth; chemokine; glomerulosclerosis; hypertension treatment; hypertensive; improved; insight; kidney vascular structure; member; military veteran; novel; novel strategies; podocyte; response; transcription factor; transplant model; vascular inflammation

Hypertensive nephropathy is a common cause of chronic kidney disease (CKD) and is the second leading cause of end-stage kidney disease (ESKD). The prevalence of CKD is significantly higher than the general population and demonstrate progressive loss of kidney function over time, more attention to the underlying mechanisms of hypertensive nephropathy are required. Remodeling of the afferent arterioles and accompanying glomerulosclerosis are hallmarks of human hypertensive nephropathy. Despite extensive investigation, there remain gaps in understanding why some hypertensive patients develop ESKD, while others do not. The molecular pathogenesis of the arteriolar remodeling in hypertensive nephropathy would provide clues to this susceptibility, but the multiple variables that associate with the human condition limit the ability to provide definitive conclusions. Insight into the molecular basis of renal microvascular remodeling may therefore be gained through the study of relevant animal models, in particular the Dahl salt-sensitive (SS) rat, a well-characterized model of hypertensive nephropathy. Our previous studies, which are described in detail in this application, uncovered an intrinsic defect in the structural/functional relationship of the renal microvasculature of SS rats occurring with increases in blood pressure. Preliminary and published studies revealed that hypertension rapidly upregulated expression of both matrix metalloproteinase-9 (MMP-9) and Chemokine (C-C motif) Ligand 2 (CCL2), a potent pro-inflammatory chemokine, in kidney microvasculature of SS rats. We further confirmed that ED-1-positive macrophages collected around the microvessels of hypertensive SS rats. Our combined findings support the working hypothesis that hypertension-induced kidney disease in SS rats is initiated by glomerular injury mediated by microvascular smooth muscle production of a milieu that promotes inflammation, remodeling, and autoregulatory impairment (Fig. 1). We propose 2 aims: Aim 1: Determine the novel mechanisms of renal microvascular remodeling and autoregulatory dysfunction in SS rats. Hypothesis: MMP-9 mediates afferent arteriolar remodeling and impairment of the myogenic response during the development of hypertension. 1.1 Assess renal afferent arteriolar remodeling and autoregulatory behavior and smooth muscle pathobiology of SSMmp9-/- rats. 1.2 Describe the role of kidney-specific versus systemic expression of MMP-9 in microvascular remodeling using a kidney transplant model. Aim 2: Define the mechanisms of the renal microvascular inflammatory process on hypertensive nephropathy in SS rats. Hypothesis: CCL2 is integrally involved in renal microvascular remodeling and autoregulatory impairment in hypertensive SS rats. 2.1 Describe the role of CCL2 in microvascular inflammation and autoregulation in SSCcl2-/- rats. 2.2 Determine the microvascular mechanism of kidney-specific versus systemic expression of CCL2 in hypertensive nephropathy using a model of kidney transplantation. By focusing on the molecular pathogenesis of renal microvascular inflammation and remodeling, impaired autoregulatory response to hypertension and glomerular injury, these studies will improve understanding of the molecular basis of CKD and ESKD from hypertension.

高血压肾病是慢性肾脏疾病（CKD）的常见原因，是 终阶段肾脏疾病（ESKD）的第二大原因。 CKD的患病率是 明显高于一般人群，并证明了肾脏的进行性损失 随着时间的流逝，功能更多地关注高血压肾病的潜在机制 需要。传入小动脉的重塑和随附的肾小球硬化是 人类高血压肾病的标志。尽管进行了广泛的调查，但仍有 理解为什么某些高血压患者会发展ESKD的差距，而另一些则没有。 高血压肾病中小动脉重塑的分子发病机理将 为这种敏感性提供线索，但是与人类相关的多个变量 条件限制了提供明确结论的能力。洞悉分子基础 因此，可以通过研究相关动物来获得肾脏微血管重塑 模型，尤其是Dahl盐敏感（SS）大鼠，这是一种高血压的良好特征模型 肾病。我们以前的研究（在本应用程序中详细描述）发现了 SS肾脏微脉管系统的结构/功能关系中的固有缺陷 随着血压升高而发生的大鼠。初步和发表的研究表明， 高血压迅速上调金属蛋白酶9（MMP-9）和 趋化因子（C-C基序）配体2（CCL2），一种有效的促炎性趋化因子，肾脏 SS大鼠的微脉管系统。我们进一步证实了收集的ED-1阳性巨噬细胞 周围的高血压SS大鼠微血管周围。我们的结合发现支持工作 假设肾小球引发了高血压诱导的SS大鼠肾脏疾病 促进的环境的微血管平滑肌产生的损伤 炎症，重塑和自动调节障碍（图1）。我们提出2个目标： 目标1：确定肾脏微血管重塑和自动调节的新型机制 SS大鼠功能障碍。假设：MMP-9介导传入小动脉的重塑和 高血压发育过程中肌原反应的损害。 1.1评估肾脏传入小动脉重塑和自动调节行为和平滑 SSMMP9 - / - 大鼠的肌肉病理生物学。 1.2描述MMP-9在肾脏特异性与全身表达的作用 使用肾脏移植模型进行微血管重塑。 AIM 2：定义肾脏微血管炎症过程的机制 SS大鼠的高血压肾病。假设：CCL2与肾脏积极参与 高血压SS大鼠的微血管重塑和自动调节损伤。 2.1描述CCL2在微血管炎症和自动调节中的作用 SSCCL2 - / - 大鼠。 2.2确定肾脏特异性与全身性的微血管机理 使用肾脏模型在高血压肾病中CCL2的表达 移植。 通过关注肾脏微血管炎症和重塑的分子发病机理， 对高血压和肾小球损伤的自调反应受损，这些研究将 提高高血压对CKD和ESKD的分子基础的理解。