Renal Medullary Stem Cell Niche in Salt Sensitive Hypertension

盐敏感性高血压中的肾髓质干细胞生态位

• 批准号: 8207205
• 负责人: Ningjun Li
• 金额: $ 37.38万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207205
• 关键词: Address; Adult; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Attenuated; Behavior; Blood Pressure; Blood Vessels; Body Fluids; Cell Aging; Cells; Data; Defect; Development; Disease; Ensure; Excretory function; Face; Failure; Fibroblast Growth Factor 2; Fibrosis; Fluid Balance; Functional disorder; Generations; Genetic Programming; Glomerulonephritis; Homeostasis; Hypertension; Impairment; Inflammation; Inflammatory; Injury; Kidney; Kidney Diseases; Lead; Maintenance; Mediating; Molecular; Normal Cell; Organ; Pathogenesis; Play; Rattus; Regulation; Renal function; Reporting; Resources; Role; Signal Transduction; Sodium; Sodium Chloride; Sprague-Dawley Rats; Stem cells; Testing; Tubular formation; Work; base; cell behavior; hypoxia inducible factor 1; improved; in vivo; insight; interstitial; kidney cell; kidney medulla; normotensive; novel therapeutics; repaired; response; salt intake; salt sensitive; self-renewal; stem; stem cell biology; stem cell differentiation; stem cell niche

The specialized microenvironment where the stem cells reside in vivo is termed stem cell niche, which is critical for the maintenance, self-renewal and differentiation of stem cells by providing extrinsic regulators. Renal medulla has recently been identified as a niche for adult kidney stem cells and these renal medullary stem cells are importantly involved in the normal structural and functional maintenance in the renal medulla. It is well known that the renal medulla plays an important role in the regulation of sodium excretion and that dysfunctions in the renal medulla are involved in salt-sensitive hypertension. We wondered whether the stem cell niche in the renal medulla, through regulating the behavior of stem cells, contributes to the maintenance of normal functional integrity in this kidney region and thereby to the long-term control of arterial blood pressure, and whether salt-sensitive hypertension is associated with the impairment of stem cell resource or niche in the renal medulla. In preliminary studies, we found that the level of an important stem cell niche factor, fibroblast growth factor-2 (FGF2), the number of CD133 positive stem cells and their responses to high salt intake were significantly decreased in the renal medulla in Dahl salt-sensitive hypertensive (Dahl S) rats compared with normotensive rats. It was also found that the decreased FGF2 level was associated with a deficiency in hypoxia-inducible factor (HIF)-1¿ and that improving stem cell niche function decreased pro-inflammatory factors in the renal medulla and attenuated salt-sensitive hypertension in Dahl S rats. These data indicate that a defect of stem cell niche may lead to abnormal generation, mobilization and differentiation of stem cells in the renal medulla and thereby lead to a failure of maintenance of renal medullary structural and functional integrity in face to high salt challenge, ultimately resulting in salt-sensitive hypertension in Dahl S rats. Based on these findings, we hypothesize that the renal medullary stem cell niche plays a critical role in the regulation of renal medullary function and the defect of such stem cell niche contributes to the development of hypertension in Dahl S rats. To test this hypothesis, we will first determine whether FGF2 regulation of stem cell behavior in the renal medulla contributes to the regulation of renal medullary function and whether a defect of this stem cell niche factor mediates the development of salt-sensitive hypertension in Dahl S rats. We will then explore the mechanisms causing the defect of the stem cell niche in the renal medulla of Dahl S rats by determining whether impaired HIF-1¿ and consequent decreases in FGF-2 levels contribute to the deficiency of this medullary stem cell niche. Finally, we will determine how the defect of renal medullary stem cell niche produces renal medullary dysfunction and hypertension in Dahl S rats, focusing on the insufficiency of stem cell-mediated anti-inflammatory actions in the renal medulla. The results from these proposed studies will define an important cellular/molecular mechanism mediating renal medullary adaptation to high salt intake and provide new insights into the stem cell-associated pathogenesis of salt-sensitive hypertension.

干细胞在体内驻留的专门微环境被称为干细胞龛， 通过提供外源性调节因子，对干细胞的维持、自我更新和分化至关重要。 肾髓质最近已被确定为成人肾干细胞的小生境，这些肾髓质干细胞可在肾髓质中生长。 干细胞在肾髓质的正常结构和功能维持中起重要作用。它 众所周知，肾髓质在钠排泄的调节中起重要作用， 肾髓质的功能障碍与盐敏感性高血压有关。我们想知道茎是否 肾髓质中的细胞龛，通过调节干细胞的行为，有助于维持 该肾脏区域的正常功能完整性，从而长期控制动脉血压， 以及盐敏感性高血压是否与干细胞资源或微生态位受损有关。 肾髓质在初步研究中，我们发现一个重要的干细胞生态位因子成纤维细胞的水平， 生长因子-2（FGF 2），CD 133阳性干细胞的数量及其对高盐摄入的反应， Dahl盐敏感性高血压（Dahl S）大鼠的肾髓质中， 正常血压大鼠。研究还发现，FGF 2水平的降低与以下因素的缺乏有关： 缺氧诱导因子（HIF）-1和改善干细胞生态位功能降低促炎性细胞因子（HIF-1）表达， Dahl S大鼠肾髓质中的因子和衰减的盐敏感性高血压。这些数据表明 干细胞龛的缺陷可能导致干细胞在干细胞中的异常生成、动员和分化。 从而导致肾髓质结构和功能完整性的维持失败 在高盐的挑战，最终导致盐敏感性高血压的Dahl S大鼠。基于这些 研究结果，我们假设肾髓质干细胞龛在肾功能的调节中起着关键作用。 髓质功能和这种干细胞龛的缺陷有助于高血压的发展， 达尔S老鼠。为了验证这一假设，我们将首先确定FGF 2是否调节干细胞的行为， 肾髓质有助于肾髓质功能的调节， 小生境因子介导Dahl S大鼠盐敏感性高血压的发展。然后我们将探索 通过测定Dahl S大鼠肾髓质干细胞龛缺陷的机制 HIF-1受损和随之而来的FGF-2水平下降是否导致这种缺陷， 骨髓干细胞龛最后，我们将确定肾髓质干细胞龛的缺陷如何 在Dahl S大鼠中产生肾髓质功能障碍和高血压，重点是干细胞功能不全 肾髓质中细胞介导的抗炎作用。这些拟议研究的结果将 定义了介导肾髓质适应高盐摄入的重要细胞/分子机制， 为盐敏感性高血压的干细胞相关发病机制提供了新的见解。