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.

干细胞在体内存在的特殊微环境称为干细胞生态位，即 通过提供外在调节因子，对于干细胞的维持、自我更新和分化至关重要。 肾髓质最近被确定为成体肾干细胞的生态位，这些肾髓质 干细胞重要地参与肾髓质的正常结构和功能维持。它 众所周知，肾髓质在钠排泄的调节中起着重要作用， 盐敏感性高血压涉及肾髓质功能障碍。我们想知道茎是否 肾髓质中的细胞生态位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， 盐敏感性高血压是否与干细胞资源或生态位受损有关 肾髓质。在初步研究中，我们发现一种重要的干细胞生态位因子——成纤维细胞的水平 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 与 Dahl 盐敏感性高血压 (Dahl S) 大鼠相比，其肾髓质显着减少 血压正常的大鼠。研究还发现，FGF2 水平降低与缺乏 缺氧诱导因子 (HIF)-1¿ 以及改善干细胞生态位功能可降低促炎作用 Dahl S 大鼠肾髓质因素和减轻盐敏感性高血压。这些数据表明 干细胞生态位的缺陷可能导致干细胞的异常生成、动员和分化。 肾髓质，从而导致维持肾髓质结构和功能完整性的失败 面对高盐挑战，最终导致 Dahl S 大鼠出现盐敏感性高血压。基于这些 研究结果表明，我们假设肾髓质干细胞生态位在肾功能的调节中发挥着关键作用。 髓质功能和干细胞生态位的缺陷导致高血压的发生 达尔 S 大鼠。为了检验这一假设，我们首先确定 FGF2 是否在干细胞行为中发挥调节作用。 肾髓质有助于肾髓质功能的调节以及该干细胞是否存在缺陷 生态位因子介导 Dahl S 大鼠盐敏感性高血压的发生。然后我们将探索 通过确定导致 Dahl S 大鼠肾髓质干细胞生态位缺陷的机制 HIF-1 受损以及随之而来的 FGF-2 水平下降是否会导致这种缺陷 髓质干细胞生态位。最后，我们将确定肾髓质干细胞生态位的缺陷如何 在 Dahl S 大鼠中产生肾髓质功能障碍和高血压，重点关注干细胞供血不足 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新的见解。