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: 8024001
• 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/8024001
• 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; Hypoxia Inducible Factor; 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

DESCRIPTION (provided by applicant): 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)-11 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-11 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. PUBLIC HEALTH RELEVANCE: A deep kidney region called the renal medulla has been identified as a stem cell niche, a specialized microenvironment where the adult kidney stem cells reside. The important niche function to regulate stem cell behavior maintains the renewal of kidney cells in the renal medulla, which is critical for the kidney to handle salt and body fluid balance and thereby to keep the arterial blood pressure normal. Defect of stem cell niche causes malfunction of these stem cells and leads to high blood pressure. All these will be clarified in this proposal. When the studies planed in this grant application are completed, new therapeutic strategies associated with stem cell activation could be developed for the treatment of high blood pressure.

描述（由申请人提供）：干细胞在体内生存的特殊微环境被称为干细胞生态位，它通过提供外部调节剂对干细胞的维持、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，这些肾髓质干细胞在肾髓质的正常结构和功能维持中起重要作用。众所周知，肾髓质在钠排泄的调节中起着重要作用，并且肾髓质功能障碍与盐敏感性高血压有关。我们想知道肾髓质中的干细胞生态位是否通过调节干细胞的行为，有助于维持该肾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肾髓质中干细胞资源或生态位的损害有关。在初步研究中，我们发现与正常血压大鼠相比，达尔盐敏感型高血压（Dahl S）大鼠肾髓质中重要的干细胞生态位因子成纤维细胞生长因子-2 （FGF2）水平、CD133阳性干细胞数量及其对高盐摄入的反应显著降低。研究还发现，FGF2水平的降低与缺氧诱导因子(HIF)-11的缺乏有关，而干细胞生态位功能的改善可降低肾髓质中的促炎因子，减轻Dahl S大鼠的盐敏感性高血压。这些数据提示，干细胞生态位缺陷可能导致肾髓质干细胞产生、动员和分化异常，从而导致肾髓质结构和功能完整性在面对高盐挑战时无法维持，最终导致Dahl S大鼠盐敏感性高血压。基于这些发现，我们推测肾髓质干细胞生态位在肾髓质功能的调节中起着关键作用，而肾髓质干细胞生态位的缺陷参与了Dahl S大鼠高血压的发生。为了验证这一假设，我们将首先确定FGF2对肾髓质干细胞行为的调节是否有助于肾髓质功能的调节，以及这种干细胞生态位因子的缺陷是否介导了Dahl S大鼠盐敏感性高血压的发生。然后，我们将通过确定HIF-11受损和随之而来的FGF-2水平下降是否导致了这种髓质干细胞生态位的缺乏，来探索导致Dahl S大鼠肾髓质干细胞生态位缺陷的机制。最后，我们将确定肾髓质干细胞生态位缺陷如何导致Dahl S大鼠肾髓质功能障碍和高血压，重点关注肾髓质干细胞介导的抗炎作用不足。这些研究的结果将定义一个重要的细胞/分子机制，介导肾髓质对高盐摄入的适应，并为盐敏感性高血压的干细胞相关发病机制提供新的见解。