Renal Medullary Stem Cell Niche in Salt Sensitive Hypertension

描述（由申请人提供）：干细胞在体内驻留的专门微环境称为干细胞龛，其通过提供外源性调节剂对干细胞的维持、自我更新和分化至关重要。肾髓质是成体肾干细胞的重要聚集区，这些肾髓质干细胞在维持肾髓质正常的结构和功能中起着重要作用。众所周知，肾髓质在钠排泄的调节中起重要作用，并且肾髓质的功能障碍涉及盐敏感性高血压。我们想知道肾髓质中的干细胞龛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龛的损害有关。在初步研究中，我们发现，一个重要的干细胞生态位因子，成纤维细胞生长因子-2（FGF 2）的水平，CD 133阳性干细胞的数量和它们对高盐摄入的反应显着降低，在肾髓质Dahl盐敏感性高血压（Dahl S）大鼠与正常血压大鼠相比。还发现FGF 2水平的降低与缺氧诱导因子（HIF）-11的缺乏有关，并且改善干细胞生态位功能降低了Dahl S大鼠肾髓质中的促炎因子并减弱了盐敏感性高血压。这些数据表明，干细胞生态位的缺陷可能会导致异常的生成，动员和分化的干细胞在肾髓质，从而导致肾髓质的结构和功能的完整性，面对高盐的挑战，最终导致盐敏感性高血压在Dahl S大鼠。基于这些发现，我们推测，肾髓质干细胞龛在肾髓质功能的调节中起着至关重要的作用，这种干细胞龛的缺陷有助于Dahl S大鼠高血压的发展。为了验证这一假设，我们将首先确定是否FGF 2调节干细胞在肾髓质的行为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展。然后，我们将探讨Dahl S大鼠肾髓质干细胞龛缺陷的机制，确定是否受损的HIF-11和随之而来的FGF-2水平的降低导致这种髓质干细胞龛的缺陷。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，重点关注干细胞介导的抗炎作用在肾髓质中的不足。这些研究的结果将确定一个重要的细胞/分子机制介导肾髓质适应高盐摄入，并提供新的见解干细胞相关的盐敏感性高血压的发病机制。 公共卫生相关性：肾脏深部区域称为肾髓质，已被确定为干细胞龛，这是成体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维持肾髓质中肾细胞的更新，这对于肾脏处理盐和体液平衡并从而保持动脉血压正常至关重要。干细胞生态位的缺陷导致这些干细胞的功能障碍，并导致高血压。所有这些都将在本提案中得到澄清。当这项资助申请中计划的研究完成时，可以开发与干细胞活化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.