Melanocortin therapy ameliorates podocytopathy and proteinuria in experimental focal segmental glomerulosclerosis involving a podocyte specific non-MC1R-mediated melanocortinergic signaling.
Melanocortin therapy ameliorates podocytopathy and proteinuria in experimental focal segmental glomerulosclerosis involving a podocyte specific non-MC1R-mediated melanocortinergic signaling.
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黑皮质素治疗可改善实验性局灶节段性肾小球硬化症中的足细胞病和蛋白尿，涉及足细胞特异性非 MC1R 介导的黑皮质素能信号传导
DOI：
10.1042/cs20200016
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发表时间：
2020-04-17
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
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作者：
促肾上腺皮质激素在诱导激素抵抗型肾病综合征缓解方面的临床效果表明，黑皮质激素具有不依赖于类固醇生成的抗蛋白尿活性。然而，哪些黑素皮质素受体(MCR)传递了这种有益的效应，以及是否涉及全身或足细胞特有的机制仍不确定。在体内，野生型(WT)小鼠在阿霉素刺激后出现严重的蛋白尿和肾功能障碍，并伴有局灶性节段性肾小球硬化(FSGS)和足细胞病变，其特征是足菌素和突触素丢失，足细胞减少和电子显微镜下广泛的足突消失。NDP-MSH可显著减轻上述病理改变，NDP-MSH是一种有效的非激素性泛MCR激动剂。令人惊讶的是，MC1R缺失小鼠的MC1R缺陷几乎没有影响阿霉素引起的损伤的严重程度。此外，NDP-MSH的有益作用在MC1R缺失的小鼠中完全保留，表明MC1R可能不是保护作用所必需的。直接的足细胞效应似乎有助于NDP-MSH的有益效果，因为NDP-MSH可减轻阿霉素诱导的WT小鼠原代足细胞的细胞病变症状，包括细胞凋亡、足细胞标志物的丢失、足细胞损伤标志物desmin的从头表达、肌动蛋白细胞骨架紊乱和足细胞过度运动。与体内研究结果一致，NDP-MSH的足部保护活性在MC1R缺失的足细胞中完全保存。从机制上讲，MC1R的表达主要分布于肾小球内皮细胞，而在体内和体外足细胞中的表达很少，提示MC1R信号不太可能参与足细胞的直接保护。因此，黑素皮质素治疗至少部分地通过足细胞特异性的非MC1R介导的黑素皮质素能信号来保护足细胞损伤，并改善实验性FSGS的蛋白尿和肾小球病变。
The clinical effectiveness of adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of melanocortins. However, which melanocortin receptors (MCR) convey this beneficial effect and if systemic or podocyte-specific mechanisms are involved remain uncertain. In vivo, wild-type (WT) mice developed heavy proteinuria and kidney dysfunction following Adriamycin insult, concomitant with focal segmental glomerulosclerosis (FSGS) and podocytopathy, marked by loss of podocin and synaptopodin, podocytopenia and extensive foot process effacement on electron microscopy. All these pathologic findings were prominently attenuated by NDP-MSH, a potent non-steroidogenic pan-MCR agonist. Surprisingly, MC1R deficiency in MC1R-null mice barely affected the severity of Adriamycin-elicited injury. Moreover, the beneficial effect of NDP-MSH was completely preserved in MC1R-null mice, suggesting that MC1R is likely non-essential for the protective action. A direct podocyte effect seems to contribute to the beneficial effect of NDP-MSH, because Adriamycin-inflicted cytopathic signs in primary podocytes prepared from WT mice were all mitigated by NDP-MSH, including apoptosis, loss of podocyte markers, de novo expression of the podocyte injury marker desmin, actin cytoskeleton derangement and podocyte hypermotility. Consistent with in vivo findings, the podoprotective activity of NDP-MSH was fully preserved in MC1R-null podocytes. Mechanistically, MC1R expression was predominantly distributed to glomerular endothelial cells in glomeruli but negligibly noted in podocytes in vivo and in vitro, suggesting that MC1R signaling is unlikely involved in direct podocyte protection. Ergo, melanocortin therapy protects against podocyte injury and ameliorates proteinuria and glomerulopathy in experimental FSGS, at least in part, via a podocyte-specific non-MC1R-mediated melanocortinergic signaling.
影响因子：
3.9
作者：
Anwar S;Larson DS;Naimi N;Ashraf M;Culiberk N;Liapis H;Wei C;Reiser J;Brennan DC
通讯作者：
Brennan DC