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: 8386965
• 负责人: Ningjun Li
• 金额: $ 35.58万
• 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/8386965
• 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.

干细胞在体内居住的专门微环境称为干细胞生态位，这是 通过提供外部调节剂来维持，自我更新和干细胞的分化至关重要。 肾脏髓质最近被确定为成年肾脏干细胞的利基市场，这些肾脏髓质 干细胞重要地参与了肾髓质的正常结构和功能维持。 众所周知，肾髓质在调节钠排泄中起着重要作用，并且 肾脏髓质的功能障碍参与盐敏感的高血压。我们想知道茎是否 通过调节，肾脏髓质中的细胞生态位，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， 以及盐敏感的高血压是否与干细胞资源的损害或利基市场有关 肾髓质。在初步研究中，我们发现重要的干细胞生态位因子的水平，成纤维细胞 生长因子2（FGF2），CD133阳性干细胞的数量及其对高盐摄入的反应是 达尔盐敏感高血压（Dahl S）大鼠的肾髓质的肾脏髓质显着降低 正常的大鼠。还发现，FGF2水平下降与缺陷有关 低氧诱导因子（HIF）-1-，改善干细胞生态位功能降低了促炎 Dahl s大鼠肾脏髓质和减弱盐敏感性高血压的因素。这些数据表明 干细胞生态位缺陷可能导致异常产生，动员和干细胞分化 肾脏髓质，从而导致肾脏髓质结构和功能完整性的维持失败 面对高盐的挑战，最终导致Dahl S大鼠的盐敏感性高血压。基于这些 调查结果，我们假设肾脏髓质干细胞小裂在肾脏的调节中起着关键作用 髓质功能和这种干细胞生态位的缺陷有助于在 达尔的老鼠。为了检验这一假设，我们将首先确定FGF2在 肾髓质有助于调节肾功能以及该干细胞缺陷是否 小裂因子介导Dahl S大鼠中盐敏感性高血压的发展。然后，我们将探索 通过确定，导致干细胞小裂缺陷的机制通过确定 HIF-1损伤以及随之而来的FGF-2水平下降是否有助于缺乏 髓质干细胞生态位。最后，我们将确定肾脏髓质干细胞小众的缺陷 在Dahl的大鼠中产生肾脏髓质功能障碍和高血压，重点是茎的不足 细胞介导的肾脏髓质抗炎作用。这些拟议的研究的结果将 定义一个重要的细胞/分子机制，介导肾脏髓质适应高盐的摄入量和 提供有关盐敏感性高血压的干细胞相关发病机理的新见解。