Pericyte-endothelial cross talk in vascular stability after kidney injury

描述（申请人提供）：周细胞，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，稳态，病理和再生中的功能才刚刚开始被充分认识。在其他器官和癌症生长中，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、生长和稳定提供关键的分子信号。我们实验室最近的研究已经确定肾小管周围毛细血管的周细胞是主要的肌成纤维细胞前体，因此是负责纤维形成的细胞。肾损伤导致周细胞脱离和远离小管周围毛细血管，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小管周围毛细血管不稳定，屏障功能受损并退化，导致毛细血管稀疏。因此，导致器官缺血的毛细血管稀疏与纤维发生有着内在的联系。然而，周细胞脱离和迁移并不一定是永久性的，预防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，通过血管内皮生长因子受体2 （VEGFR2）的周细胞到内皮的信号传导是调节周细胞脱离和肾脏疾病进展的中心途径。直接根据ARRA挑战基金资助的工作，并根据损伤后小管周围毛细血管再生失败可能导致间质纤维化和慢性肾损伤的中心假设，我们将进行以下研究。目的1：采用新的遗传消融方法，确定小鼠肾脏周细胞在稳态和损伤反应中的功能。确定周细胞源性TIMP3和ADAMTS1在微血管稳定性和VEGF受体信号通路调控中的作用。将周细胞来源的VEGFA定义为自发和诱导肾脏疾病进展的决定因素。

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.