Department of Medicine, Division of Nephrology McMaster University and St Joseph's Healthcare Hamilton, 50 Charlton Ave, East Hamilton, Ontario, Canada, L8N 4A6.
Circ Res. 2011 Mar 4;108(5):629-42. doi: 10.1161/CIRCRESAHA.110.226803.
Synthesis of transmembrane and secretory proteins occurs within the endoplasmic reticulum (ER) and is extremely important in the normal functioning of both the heart and kidney. The dysregulation of protein synthesis/processing within the ER causes the accumulation of unfolded proteins, thereby leading to ER stress and the activation of the unfolded protein response. Sarcoplasmic reticulum/ER Ca2+ disequilibrium can lead to cardiac hypertrophy via cytosolic Ca2+ elevation and stimulation of the Ca2+/calmodulin, calcineurin, NF-AT3 pathway. Although cardiac hypertrophy may be initially adaptive, prolonged or severe ER stress resulting from the increased protein synthesis associated with cardiac hypertrophy can lead to apoptosis of cardiac myocytes and result in reduced cardiac output and chronic heart failure. The failing heart has a dramatic effect on renal function because of inadequate perfusion and stimulates the release of many neurohumoral factors that may lead to further ER stress within the heart, including angiotensin II and arginine-vasopressin. Renal failure attributable to proteinuria and uremia also induces ER stress within the kidney, which contributes to the transformation of tubular epithelial cells to a fibroblast-like phenotype, fibrosis, and tubular cell apoptosis, further diminishing renal function. As a consequence, cardiorenal syndrome may develop into a vicious circle with poor prognosis. New therapeutic modalities to alleviate ER stress through stimulation of the cytoprotective components of the unfolded protein response, including GRP78 upregulation and eukaryotic initiation factor 2α phosphorylation, may hold promise to reduce the high morbidity and mortality associated with cardiorenal syndrome.
跨膜蛋白和分泌蛋白的合成发生在内质网（ER）中，这对心脏和肾脏的正常功能非常重要。ER 中蛋白质合成/加工的失调会导致未折叠蛋白质的积累，从而导致 ER 应激和未折叠蛋白反应的激活。肌浆网/ER Ca2+失衡可通过胞质 Ca2+升高和 Ca2+/钙调蛋白、钙调神经磷酸酶、NF-AT3 途径的刺激导致心脏肥大。虽然心脏肥大最初可能是适应性的，但与心脏肥大相关的蛋白质合成增加导致的长期或严重的 ER 应激可导致心肌细胞凋亡，导致心输出量减少和慢性心力衰竭。衰竭的心脏由于灌注不足对肾功能有巨大影响，并刺激许多神经激素因子的释放，这些因子可能导致心脏内进一步的 ER 应激，包括血管紧张素 II 和精氨酸加压素。蛋白尿和尿毒症引起的肾功能衰竭也会导致肾脏内 ER 应激，导致肾小管上皮细胞向成纤维样表型、纤维化和肾小管细胞凋亡转化，进一步降低肾功能。因此，心肾综合征可能发展成预后不良的恶性循环。通过刺激未折叠蛋白反应的细胞保护成分，包括 GRP78 上调和真核起始因子 2α 磷酸化，来减轻 ER 应激的新治疗方法可能有希望降低与心肾综合征相关的高发病率和死亡率。
