Renal Medullary Stem Cell Niche in Salt Sensitive Hypertension

描述(申请人提供)：干细胞驻留在体内的特殊微环境被称为干细胞利基，它通过提供外部调节因子对干细胞的维持、自我更新和分化至关重要。近来，肾髓质被认为是成人肾干细胞的利基，这些肾髓质干细胞在肾髓质的正常结构和功能维持中起着重要作用。众所周知，肾髓质在钠排泄调节中起着重要作用，肾髓质功能障碍与盐敏感型高血压有关。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，有助于维持肾脏区域的正常功能完整性，从而有助于长期控制动脉血压，以及盐敏感型高血压是否与肾髓质干细胞来源或生态位受损有关。我们在前期研究中发现，与正常血压大鼠相比，Dahl盐敏感型高血压大鼠(Dahl S)肾髓质中重要的干细胞巢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量的反应均显著降低。研究还发现，成纤维细胞生长因子2水平的降低与缺氧诱导因子-11的缺乏有关，干细胞巢功能的改善减少了肾髓质中的促炎因子，从而减轻了S大鼠的盐敏性高血压。提示干细胞生态位缺陷可能导致肾髓质干细胞的产生、动员和分化异常，从而导致肾脏髓质结构和功能的完整性在高盐胁迫下无法维持，最终导致Dahl S大鼠盐敏感型高血压。根据这些发现，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，这种干细胞生态位的缺陷参与了Dahl-S大鼠高血压的发生发展。为了验证这一假说，我们将首先确定肾髓质干细胞行为的成纤维细胞生长因子2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大鼠盐敏感型高血压的发展。然后，我们将通过确定HIF-11受损和随之而来的成纤维细胞生长因子-2水平的降低是否导致Dahl S大鼠肾髓质干细胞生态位的缺陷，来探讨导致该干细胞生态位缺陷的机制。最后，我们将重点研究肾髓质干细胞介导的抗炎作用不足，确定肾髓质干细胞巢缺陷如何导致Dahl S大鼠肾髓质功能障碍和高血压。这些拟议的研究结果将确定一个重要的细胞/分子机制，介导肾脏髓质对高盐摄入量的适应，并为盐敏感型高血压的干细胞相关发病机制提供新的见解。 与公共卫生相关：肾深部区域被称为肾髓质，已被确定为干细胞利基，这是成人肾脏干细胞驻留的专门微环境。调节干细胞行为的重要生态位功能是维持肾髓质中肾细胞的更新，这对肾脏处理盐分和体液平衡从而保持正常的动脉血压至关重要。干细胞巢的缺陷会导致这些干细胞的功能障碍，并导致高血压。所有这些都将在这项提案中得到澄清。当这项拨款申请中计划的研究完成后，可以开发与干细胞激活相关的新治疗策略来治疗高血压。

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.