Vascular Mechanisms of Hypertensive Nephropathy

高血压肾病是慢性肾脏疾病(CKD)的常见原因之一，也是 终末期肾病(ESKD)的第二大原因。慢性肾脏病的患病率为 显著高于一般人群，并表现为进行性肾功能丧失 随着时间的推移，更多地关注高血压肾病的潜在机制 都是必需的。传入小动脉重塑和伴随的肾小球硬化 人类高血压肾病的特征。尽管进行了广泛的调查，但仍有 在理解为什么一些高血压患者会患上ESKD，而其他患者不会的原因上存在差距。 高血压肾病小动脉重构的分子发病机制 提供了这种易感性的线索，但与人类 条件限制了提供明确结论的能力。洞察分子基础 因此，通过对相关动物的研究，可以获得肾微血管重塑 模型，特别是Dahl盐敏感(SS)大鼠，这是一种具有良好特征的高血压模型 肾病。我们之前的研究，在本申请中详细描述，发现 SS肾微血管结构/功能关系的固有缺陷 血压升高的大鼠。初步和已发表的研究表明， 高血压迅速上调基质金属蛋白酶-9和基质金属蛋白酶-9表达 趋化因子(C-C基序)配体2(CCL2)，一种有效的促炎趋化因子，在肾脏中 SS大鼠的微血管构筑。我们进一步证实收集到的ED-1阳性巨噬细胞 在高血压SS大鼠的微血管周围。我们的综合发现支持这项工作 SS大鼠高血压肾病始于肾小球的假说 促进微血管平滑肌产生的环境介导的损伤 炎症、重塑和自我调节功能受损(图1)。我们提出两个目标： 目的1：确定肾微血管重塑和自身调节的新机制 SS大鼠的功能障碍。假设：基质金属蛋白酶-9介导传入小动脉重构和 高血压发展过程中的肌源性反应受损。 1.1评估肾传入小动脉重构和自我调节行为，并保持顺畅 SSMmp9-/-大鼠的肌肉病理生物学。 1.2描述基质金属蛋白酶-9在肾脏特异性和系统性表达中的作用 使用肾移植模型的微血管重塑。 目的2：明确肾微血管炎症过程的机制。 SS大鼠高血压肾病模型的建立。假设：CCL2与肾脏密切相关 高血压SS大鼠微血管重塑与自身调节功能障碍。 2.1描述CCL2在微血管炎症和自身调节中的作用 SSCCl2-/-大鼠。 2.2确定肾脏特异性与全身性的微血管机制 CCL2在高血压性肾病肾脏模型中的表达 移植。 通过重点研究肾微血管炎症和重塑的分子发病机制， 高血压和肾小球损伤的自我调节反应受损，这些研究将 提高对高血压CKD和ESKD分子基础的认识。

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.