Renalase在急性肾损伤向慢性化转归中的作用及机制研究

Acute kidney injury (AKI) confers increased risk of progression to chronic kidney disease (CKD). However, there are no effective interventions to prevent the CKD progression after AKI, which is imperative to be solved for AKI therapy. It has been reported that failed tubular regeneration caused by cell cycle arrest and abnormal macrophage polarization play a crucial role in chronic progression of AKI. Renalase, a kidney-derived cytokine, functions as a pro-survival/growth factor. Previous studies of the applicant team found that renalase could exert protective effects against ischemia/reperfusion injury in various organs and could promote macrophage towards an M2 activation phenotype with anti-inflammation property. Our previous study also found that renalase deficiency was present after AKI. Based on this, the applicants speculate that renalase deficiency contribute to failed tubular regeneration after injury and reduction of M2 activation phenotype, which may accelerate progression of CKD after AKI. By using knockout mice, exogenous administration and overexpression in mice, the role of renalase in CKD progression after AKI was determined. In vivo and in vitro experiments will also be performed to elucidate the underlying mechanisms, which will provide experimental evidence for clinical therapy.

急性肾损伤（AKI）会增加慢性肾脏病（CKD）患病风险；目前临床尚无有效疗法能阻止AKI向CKD的转归，这已经成为AKI治疗亟待解决的问题。研究发现细胞增殖周期阻滞所导致的小管再生障碍及巨噬细胞亚型分化异常在AKI的慢性进展中起至关重要作用。Renalase是一种由肾脏分泌的细胞因子，能够促进细胞存活及生长；申请人团队前期发现renalase能保护多种器官缺血再灌注损伤，并促使巨噬细胞向具有抗炎作用的M2亚型细胞分化；且在AKI急性期后renalase的表达水平明显降低。基于此，申请人推测renalase缺乏可能会造成小管细胞损伤后再生障碍及M2亚型巨噬细胞的减少，从而促进AKI向CKD进展。申请人拟在小鼠中通过基因敲除、外源性补充及过表达等手段研究renalase对AKI向CKD转化的影响，并在体内外探究其发挥保护作用的机制，为临床治疗提供实验依据。

急性肾损伤会加重慢性肾脏病的风险。既往研究发现由于细胞周期阻滞引起的小管细胞再生障碍是造成AKI慢性化的重要原因。Renalase是一种由肾脏分泌的细胞因子，能够促进细胞存活及生长；基于此，申请人推测renalase缺乏可能会造成小管细胞损伤后再生障碍，从而促进AKI向CKD进展。在基金的支持下，我们利用三种AKI动物模型，观察敲除renalase对AKI后肾小管细胞再生、损伤后纤维化的影响。研究结果显示：敲除renalase可以加重多种AKI动物模型后期的肾脏病理损伤及纤维化，并且伴随着细胞周期负性条件蛋白p21的表达升高。这些结果提示renalase可能通过调控小管细胞周期起肾脏保护作用。此外，我们在基金支持下获得初步临床研究结果，正事renalase在预测急性肾损伤预后中的临床价值并获得临床基金资助。同时，我们在db/db小鼠中敲除renalase，发现敲除renalase可以加重db/db小鼠系膜细胞肥大、肾脏病理损伤；而过表达renalase可减轻db/db小鼠肾损伤。综上所述，以上研究结果进一步阐明了renalase在AKI、糖肾多种肾脏疾病中的保护作用及机制，并对其在临床中的应用进行初步探索，具有重要的科学价值及一定的临床应用前景。