心血管疾病是造成CKD死亡的最主要原因，其中左心室重构是患者心因死亡的独立致病危险因素。研究发现calcineurin/NFAT通路的过度激活在CKD心肌重构发病中起重要作用。Renalase是一种由肾脏分泌，具有心脏保护作用的细胞因子。申请人前期研究发现CKD患者存在renalase缺乏；过表达renalase可改善CKD大鼠肾功能、降低血压并延缓心肌重构。近期研究发现，细胞膜表面的PMCA4b是renalase的受体，且既往研究发现PMCA4b可通过抑制calcineurin/NFAT激活拮抗心肌肥厚。因此，申请人推测renalase通过调控PMCA4b/calcineurin/NFAT信号通路抑制心肌重构。本项目拟在CKD及左心室肥厚模型中，观察条件性敲除renalase、干预PMCA4b及无活性renalase肽段对心肌重构的影响，并在体内外探究其分子机制，为临床防治拓展新思路。

Cardiovascular diseases are the leading cause of patients with chronic kidney disease and left ventricular remodeling is an independent causal risk factor of cardiovascular death. It has been suggested that excessive activation of calcineurin/NFAT signaling pathway plays a crucial role in the pathogenesis of cardiac remodeling. Renalase, a kidney-derived cytokine, exerts cardio-protective effects. Previous studies of the applicant have found that renalase deficiency is present in CKD patients and overexpression of renalase attenuates hypertension, renal injury and cardiac remodeling in CKD rats. Recent study has reported that cellular membrane PMCA4b serves as a specific receptor for renalase. Moreover, previous study has demonstrated that PMCA4b antagonizes cardiac hypertrophy though inhibition of calcineurin/NFAT pathway. Based on this, the applicants speculate that renalase may regulate cardiac remodeling through PMCA4b/calcineurin/NFAT pathway. By using conditional knockout of renalase in tubular cells, manipulation of PMCA4b expression and renalase peptides without any intrinsic enzymatic activity, the effects of renalase on cardiac remodeling will be observed in mice of CKD and left ventricular hypertrophy models. In vivo and in vitro experiments will also be performed to elucidate the underlying mechanisms. Thus, this study will provide us a novel strategy for therapeutic intervention of cardiovascular diseases in CKD.