一项新的研究发现，在耶鲁首次发现的renalase蛋白，可以保护细胞免遭导致心脏病和肾衰竭的严重损伤。这项研究发现可能可以提供新的治疗方法，以用来保护机体避免心脏病和肾衰竭。近期这项研究成果发表在PLOS ONE杂志上。

　　一直以来，高血压、中风和糖尿病呈高发趋势，具有氧化还原活性的renalase的单核苷酸基因多态性，与这些疾病相关联。Renalase的基因敲除可引起高血压，加重急性肾缺血和心脏损伤。在野生型小鼠，不依赖于内源活性，细胞外的renalase活性就可以激活MAPK信号通路，避免急性肾损伤。因此，研究人员们希望能找到细胞外renalase的受体。

　　耶鲁医学院研究员，医学教授Gary V. Desir博士，正在研究蛋白renalase的作用机制，这种蛋白在2005年首次在Desir的实验室发现，他们将其命名为RP-220。通过在人近段肾小管细胞系HK-2上的生物素转移实验，和用质谱方法，他们鉴别出了这种蛋白的受体，一种名为PMCA4b的分子。研究人员利用免疫共沉淀和免疫共定位的方法，证实了renalase和PMCA4b的相互作用。他们还发现，renalase 和其受体PMCA4b相互作用，可以促进细胞存活。用SiRNA降低内源性的PMCA4b表达, 或者是用特异的抑制剂caloxin1b抑制renalase酶活性, 均可以减弱依赖于renalae活性的MAPK信号，从而降低细胞保护作用。但是，在对照组，表皮生长因子介导的信号不受影响，证明了PMCA4b和 renalase相互作用的特异性。

　　其他的研究已经证实，renalase有保护心脏和控制血压的作用。通过发现renalse的受体和研究清楚它的作用机制，耶鲁的研究人员可能将研发出新的治疗靶点。这项研究有助于开发出新药物，来保护肾脏和心脏，以避免这些脏器的缺血和毒性损伤。另外，他们将进一步研究renalase在癌症中的作用。

　　doi: 10.1371/journal.pone.0122932

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　　Identification of a Receptor for Extracellular Renalase

　　Ling Wang et.al

　　BACKGROUND:

　　An increased risk for developing essential hypertension, stroke and diabetes is associated with single nucleotide gene polymorphisms in renalase, a newly described secreted flavoprotein with oxidoreductase activity. Gene deletion causes hypertension, and aggravates acute ischemic kidney (AKI) and cardiac injury. Independent of its intrinsic enzymatic activities, extracellular renalase activates MAPK signaling and prevents acute kidney injury (AKI) in wild type (WT) mice. Therefore, we sought to identity the receptor for extracellular renalase.

　　METHODS AND RESULTS:

　　RP-220 is a previously identified, 20 amino acids long renalase peptide that is devoid of any intrinsic enzymatic activity, but it is equally effective as full-length recombinant renalase at protecting against toxic and ischemic injury. Using biotin transfer studies with RP-220 in the human proximal tubular cell line HK-2 and protein identification by mass spectrometry, we identified PMCA4b as a renalase binding protein. This previously characterized plasma membrane ATPase is involved in cell signaling and cardiac hypertrophy. Co-immunoprecipitation and co-immunolocalization confirmed protein-protein interaction between endogenous renalase and PMCA4b. Down-regulation of endogenous PMCA4b expression by siRNA transfection, or inhibition of its enzymatic activity by the specific peptide inhibitor caloxin1b each abrogated RP-220 dependent MAPK signaling and cytoprotection. In control studies, these maneuvers had no effect on epidermal growth factor mediated signaling, confirming specificity of the interaction between PMCA4b and renalase.

　　CONCLUSIONS:

　　PMCA4b functions as a renalase receptor, and a key mediator of renalase dependent MAPK signaling.