Pericyte-endothelial cross talk in vascular stability after kidney injury

描述(申请人提供)：周细胞，即肾小管周围毛细血管的壁细胞，直到最近才被忽视，它们在肾脏发育、内稳态、病理和再生中的作用才开始被充分认识。在其他器官中，以及在癌症生长中，周细胞在血管生成、血管稳定和毛细血管屏障功能中的关键作用现已确立。周细胞作为新生血管为内皮细胞的迁移、生长和稳定提供了关键的分子信号。我们实验室最近的研究发现，肾小管周毛细血管周细胞是肌成纤维细胞的主要前体细胞，因此该细胞负责纤维化的形成。肾脏损伤会导致周细胞脱离并从肾小管周毛细血管中迁移出来，我们称之为肌成纤维细胞。新的证据表明，由于这一过程而失去周细胞的管周毛细血管是不稳定的，具有屏障功能受损和退化，导致毛细血管稀疏。因此，导致器官缺血的毛细血管稀疏与肝纤维化有内在联系。然而，周细胞脱离和迁移不一定是永久性的，防止脱离或促进再附着可能是正常器官再生的核心。新的研究发现，周细胞通过血管内皮细胞生长因子受体2(VEGFR2)向内皮细胞传递信号是调节周细胞脱离和肾脏疾病进展的中心途径。继ARRA Challenger Grant资助的工作之后，我们将进行以下研究：损伤后不能再生肾小管周围毛细血管可能导致间质纤维化和慢性肾损伤。目的：1.采用新的遗传消融方法，研究小鼠肾脏周细胞在稳态和损伤反应中的作用目的2.确定周细胞来源的TIMP3和ADAMTS1在微血管稳定性和血管内皮生长因子受体信号转导中的作用；3.确定周细胞来源的VEGFA是自发性和诱导性肾脏疾病进展的决定因素。 公共卫生相关性：急性肾损伤、慢性肾脏疾病和终末期肾脏疾病是主要的健康负担。周细胞是肾脏的细胞，最近被描述为在肾脏疾病中发挥主要作用。在健康状态下，这些细胞滋养肾脏的小血管，但在受伤后从小血管迁移，导致这些宝贵的血管不稳定和丢失。这些研究将探讨周细胞滋养肾血管的机制，以及它们在损伤后分离并随后无法滋养的机制。通过了解这些过程，我们希望开发治疗肾脏疾病的新疗法。

DESCRIPTION (provided by applicant): Pericytes, mural cells of the kidney peritubular capillaries, have been neglected until recently, and their function in kidney development, homeostasis, pathology and regeneration is only starting to be fully appreciated. In other organs, and also in cancer growth, the crucial role of pericytes in angiogenesis, vessel stabilization and capillary barrier functions is now established. Pericytes provide key molecular signals to endothelium for endothelial migration, growth and stabilization as new vessels. Recent studies from our lab have identified pericytes of the kidney peritubular capillaries as the major myofibroblast precursor, and therefore the cell responsible for fibrogenesis. Kidney injuries lead to pericyte detachment and migration away from peritubular capillaries as cells we call myofibroblasts. New evidence indicates that peritubular capillaries, which have lost pericytes due to this process, are unstable, have impaired barrier function and regress, leading to capillary rarefaction. Therefore capillary rarefaction, which results in organ ischemia, is intrinsically linked fibrogenesis. However pericyte detachment and migration are not necessarily permanent and prevention of detachment or promotion of reattachment may be central to normal organ regeneration. New studies have identified pericyte to endothelial signaling via Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) as a central pathway in regulating pericyte detachment and kidney disease progression. Directly following on from ARRA Challenge Grant funded work and working with a central hypothesis that failure to regenerate peritubular capillaries after injury may lead to interstitial fibrosis and chronic kidney injury wewill undertake the following studies. Aim 1: Using novel genetic ablative methods, determine the function of kidney pericytes in homoeostasis and injury responses in mouse kidney Aim 2. Determine the role of pericyte-derived TIMP3 and ADAMTS1 in regulation of microvascular stability and VEGF receptor signaling Aim 3. Define pericyte-derived VEGFA as a determinant of spontaneous & induced kidney disease progression. PUBLIC HEALTH RELEVANCE: Acute Kidney Injury, Chronic Kidney Disease and End Stage Kidney Disease are major health burdens. Pericytes are cells of the kidney that have recently been descibed to play a major role in kidney disease. In health these cells nurture small blood vessels of the kidney but after injury migrate from the small vessels leading to instability and loss of these precious vessels. These studies will investigate the mechanisms by which pericytes nurture kidney blood vessels and the mechanisms by which they detach in response to injury and thereafter fail to nurture. In understanding these processes we hope to develop new therapies to treat kidney diseases.