MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy
MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy
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DOI：
10.1038/srep27589
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发表时间：
2016-06-08
影响因子：
4.6
通讯作者：
Gong, Rujun
中科院分区：
文献类型：
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作者：
Qiao, Yingjin;Berg, Anna-Lena;Gong, Rujun
使用促肾上腺皮质激素 (ACTH) 或非类固醇生成性黑皮质素肽治疗可减轻实验性肾小球疾病中的蛋白尿和肾小球损伤，并诱导患有多种肾小球疾病（甚至对类固醇耐药的患者）的肾病综合征缓解。潜在的机制仍然难以捉摸，但黑皮质素 1 受体 (MC1R) 的作用已被暗示并在此进行了研究。 4例先天性红发并因特发性膜性肾病或局灶节段性肾小球硬化引起的肾病综合征患者经基因测序证实携带MC1R显性失活突变。尽管先前存在皮质类固醇抵抗，但所有患者均对 ACTH 单药治疗有反应，并最终实现临床缓解，推断黑皮质素信号传导具有不依赖类固醇生成且非 MC1R 的抗蛋白尿作用。在验证性动物研究中，[Nle(4), D-Phe(7)]-α-黑素细胞刺激激素 (NDP-MSH)（一种强效非类固醇生成性泛黑皮质素受体激动剂）对脂多糖引起的足细胞病的保护作用在 MC1R 缺失小鼠中完全保留，其特点是白蛋白尿减少和足细胞损伤的组织学迹象减少。此外，在补充性体外研究中，NDP-MSH 在 MC1R 缺失小鼠和野生型小鼠的原代足细胞中同样减弱了脂多糖引起的细胞凋亡、运动过度和滤过屏障功能受损。总的来说，我们的研究结果表明，黑皮质素疗法通过 MC1R 独立机制，对蛋白尿性肾小球病具有减少蛋白尿和足部保护作用。
Melanocortin therapy by using adrenocorticotropic hormone (ACTH) or non-steroidogenic melanocortin peptides attenuates proteinuria and glomerular injury in experimental glomerular diseases and induces remission of nephrotic syndrome in patients with diverse glomerulopathies, even those resistant to steroids. The underlying mechanism remains elusive, but the role of melanocortin 1 receptor (MC1R) has been implicated and was examined here. Four patients with congenital red hair color and nephrotic syndrome caused by idiopathic membranous nephropathy or focal segmental glomerulosclerosis were confirmed by gene sequencing to bear dominant-negative MC1R mutations. Despite prior corticosteroid resistance, all patients responded to ACTH monotherapy and ultimately achieved clinical remission, inferring a steroidogenic-independent and MC1R-dispensable anti-proteinuric effect of melanocortin signaling. In confirmatory animal studies, the protective effect of [Nle(4), D-Phe(7)]-alpha-melanocyte stimulating hormone (NDP-MSH), a potent non-steroidogenic pan-melanocortin receptor agonist, on the lipopolysaccharide elicited podocytopathy was completely preserved in MC1R-null mice, marked by reduced albuminuria and diminished histologic signs of podocyte injury. Moreover, in complementary in vitro studies, NDP-MSH attenuated the lipopolysaccharide elicited apoptosis, hypermotility and impairment of filtration barrier function equally in primary podocytes derived from MC1R-null and wildtype mice. Collectively, our findings suggest that melanocortin therapy confers a proteinuria reducing and podoprotective effect in proteinuric glomerulopathies via MC1R-independent mechanisms.