Vascular Mechanisms of Hypertensive Nephropathy

高血压肾病是慢性肾脏疾病（CKD）的常见原因，并且是慢性肾脏疾病的主要病因。 终末期肾病（ESKD）的第二大病因。CKD的患病率是 显著高于一般人群，并表现出肾功能进行性丧失 随着时间的推移，更多的关注高血压肾病的潜在机制 are required.传入小动脉的重塑和伴随的肾小球硬化是 人类高血压肾病的标志。尽管进行了广泛的调查， 在理解为什么一些高血压患者发展ESKD，而其他人没有的差距。 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，但与人类相关的多个变量 条件限制了提供明确结论的能力。深入了解的分子基础 因此，可以通过相关动物的研究来获得肾微血管重构 模型，特别是Dahl盐敏感（SS）大鼠，一种良好表征的高血压模型， 肾病我们以前的研究，在本申请中详细描述， SS肾微血管结构/功能关系的内在缺陷 大鼠血压升高。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（MMP-9）和 趋化因子（C-C基序）配体2（CCL 2）是一种强有力的促炎趋化因子，在肾脏中 SS大鼠的微血管。我们进一步证实，收集的艾德-1阳性巨噬细胞 在高血压SS大鼠的微血管周围。我们的综合研究结果支持了 SS大鼠高血压性肾病由肾小球启动假说 由微血管平滑肌产生的环境介导的损伤 炎症、重塑和自身调节受损（图1）。我们提出两个目标： 目的1：确定肾脏微血管重构和自身调节的新机制 SS大鼠的功能障碍。假设：MMP-9介导传入小动脉重塑， 在高血压发展过程中肌原性反应受损。 1.1评估肾传入小动脉重塑和自身调节行为， SSMmp 9-/-大鼠的肌肉病理学。 1.2描述MMP-9的肾脏特异性表达与系统性表达在 使用肾移植模型进行微血管重塑。 目的2：明确肾微血管炎症过程的机制， SS大鼠高血压肾病。假设：CCL 2整体参与肾脏 高血压SS大鼠微血管重构和自身调节功能障碍。 2.1描述CCL 2在微血管炎症和自身调节中的作用， SSCcl 2-/-大鼠。 2.2确定肾脏特异性与全身性的微血管机制 CCL 2在高血压肾病中的表达 移植 通过关注肾微血管炎症和重塑的分子发病机制， 对高血压和肾小球损伤的自动调节反应受损，这些研究将 提高对高血压导致CKD和ESKD的分子基础的认识。

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.