Wanka Heike, Staar Doreen, Lutze Philipp, Peters Barbara, Hildebrandt Johanna, Beck Tim, Bäumgen Inga, Albers Alexander, Krieg Thomas, Zimmermann Katrin, Sczodrok Jaroslaw, Schäfer Simon, Hoffmann Sigrid, Peters Jörg
Department of Physiology, University Medicine of Greifswald, Greifswalder Str. 11C, D-17495, Karlsburg, Germany.
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
J Mol Med (Berl). 2016 Jan;94(1):61-9. doi: 10.1007/s00109-015-1321-z. Epub 2015 Aug 11.
In the heart, secretory renin promotes hypertrophy, apoptosis, necrosis, fibrosis, and cardiac failure through angiotensin generation from angiotensinogen. Thus, inhibitors of the renin-angiotensin system are among the most potent drugs in the treatment of cardiac failure. Renin transcripts have been identified encoding a renin isoform with unknown targets and unknown functions that are localized to the cytosol and mitochondria. We hypothesize that this isoform, in contrast to secretory renin, exerts cardioprotective effects in an angiotensin-independent manner. Cells overexpressing cytosolic renin were generated by transfection or obtained from CX(exon2-9)renin transgenic rats. Overexpression of cytosolic renin reduced the rate of necrosis in H9c2 cardiomyoblasts and in primary cardiomyocytes after glucose depletion. These effects were not mediated by angiotensin generation since an inhibitor of renin activity did not influence the in vitro effects. siRNA-mediated knockdown of endogenous cytosolic renin increased the rate of necrosis and aggravated the pro-necrotic effects of glucose depletion. Isolated perfused hearts obtained from transgenic rats overexpressing cytosolic renin exhibited a 50% reduction of infarct size after ischemia-reperfusion injury. Cytosolic renin is essential for survival, both under basal conditions and during glucose starvation. The protective effects are angiotensin-independent and contrary to the known actions of secretory renin.
A cytosolic isoform of renin with unknown functions is expressed in the heart. Cytosolic renin diminishes ischemia induced damage to the heart. The protective effects of cytosolic renin contradict the known function of secretory renin. The effects of cytosolic renin are not mediated via angiotensin generation. Renin-binding protein is a potential target for cytosolic renin.
在心脏中，分泌型肾素通过从血管紧张素原生成血管紧张素，促进心肌肥大、凋亡、坏死、纤维化和心力衰竭。因此，肾素-血管紧张素系统抑制剂是治疗心力衰竭最有效的药物之一。已鉴定出肾素转录本编码一种肾素同工型，其靶点和功能未知，定位于细胞质和线粒体。我们假设，与分泌型肾素相反，这种同工型以不依赖血管紧张素的方式发挥心脏保护作用。通过转染产生过表达细胞质肾素的细胞，或从CX（外显子2-9）肾素转基因大鼠获得。细胞质肾素的过表达降低了葡萄糖耗尽后H9c2心肌母细胞和原代心肌细胞的坏死率。这些作用不是由血管紧张素生成介导的，因为肾素活性抑制剂不影响体外作用。siRNA介导的内源性细胞质肾素敲低增加了坏死率，并加重了葡萄糖耗尽的促坏死作用。从过表达细胞质肾素的转基因大鼠获得的离体灌注心脏在缺血-再灌注损伤后梗死面积减少了50%。细胞质肾素在基础条件下和葡萄糖饥饿期间对生存至关重要。其保护作用不依赖血管紧张素，与分泌型肾素的已知作用相反。
心脏中表达一种功能未知的细胞质肾素同工型。细胞质肾素减少缺血诱导的心脏损伤。细胞质肾素的保护作用与分泌型肾素的已知功能相矛盾。细胞质肾素的作用不是通过血管紧张素生成介导的。肾素结合蛋白是细胞质肾素的潜在靶点。
