Melanocortin 1 receptor agonist protects podocytes through catalase and RhoA activation
Melanocortin 1 receptor agonist protects podocytes through catalase and RhoA activation
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DOI：
10.1152/ajprenal.00231.2015
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发表时间：
2016-05-01
影响因子：
4.2
通讯作者：
Haraldsson, Borje
中科院分区：
文献类型：
--
作者：
Elvin, Johannes;Buvall, Lisa;Haraldsson, Borje
含有促肾上腺皮质激素的药物已被用于治疗肾病综合征患者。我们之前已经证明，促肾上腺皮质激素和黑皮质素 1 受体 (MC1R) 的选择性激动剂对实验性膜性肾病具有有益作用，可减少蛋白尿、减少氧化应激并改善肾小球形态和功能。我们的假设是，足细胞中的 MC1R 激活通过促进应力纤维和维持足细胞活力而产生有益效果。为了验证这一假设，我们培养了足细胞并使用了高度特异性的 MC1R 激动剂。将足细胞置于肾病诱导剂嘌呤霉素氨基核苷中，并研究 MC1R 激活对足细胞存活、抗氧化防御和细胞骨架动力学的下游影响。为了增加反应并增强细胞内信号，足细胞被转导以过度表达 MC1R。我们发现嘌呤霉素促进足细胞中 MC1R 的表达，并且 MC1R 的激活促进过氧化氢酶活性增加并减少氧化应激，从而导致 p190RhoGAP 去磷酸化并通过 RhoA 形成应激纤维。此外，MC1R 激动剂还可防止细胞凋亡。这些机制共同保护足细胞免受嘌呤霉素的侵害。我们的研究结果强烈支持这样的假设：选择性 MC1R 激活激动剂可以保护足细胞，因此可能有助于治疗通常被认为是足细胞病的肾病综合征患者。
Drugs containing adrenocorticotropic hormone have been used as therapy for patients with nephrotic syndrome. We have previously shown that adrenocorticotropic hormone and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, and improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability. To test the hypothesis, we cultured podocytes and used highly specific agonists for MC1R. Podocytes were subjected to the nephrotic-inducing agent puromycin aminonucleoside, and downstream effects of MC1R activation on podocyte survival, antioxidant defense, and cytoskeleton dynamics were studied. To increase the response and enhance intracellular signals, podocytes were transduced to overexpress MC1R. We showed that puromycin promotes MC1R expression in podocytes and that activation of MC1R promotes an increase of catalase activity and reduces oxidative stress, which results in the dephosphorylation of p190RhoGAP and formation of stress fibers through RhoA. In addition, MC1R agonists protect against apoptosis. Together, these mechanisms protect the podocyte against puromycin. Our findings strongly support the hypothesis that selective MC1R-activating agonists protect podocytes and may therefore be useful to treat patients with nephrotic syndromes commonly considered as podocytopathies.