Secretion of the epithelial sodium channel chaperone PCSK9 from the cortical collecting duct links sodium retention with hypercholesterolemia in nephrotic syndrome.
Secretion of the epithelial sodium channel chaperone PCSK9 from the cortical collecting duct links sodium retention with hypercholesterolemia in nephrotic syndrome.
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DOI：
10.1016/j.kint.2020.06.045
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发表时间：
2020-12
影响因子：
19.6
通讯作者：
Clement LC
中科院分区：
文献类型：
--
作者：
Molina-Jijon E;Gambut S;Macé C;Avila-Casado C;Clement LC
前蛋白PCSK 9作为皮质集合管（CCD）中上皮钠通道的伴侣蛋白，在肝脏中高度表达，在高胆固醇血症的发病机制中起重要作用。正常肾脏和肠道中也存在较低水平的PCSK 9表达。在此，我们发现原发性肾小球疾病患者的CCD活检组织中PCSK 9表达增加，并探讨了其与肾病综合征高胆固醇血症的可能关系。在两种局灶性和节段性肾小球硬化模型（Rrm 2b −/−小鼠和布法罗/Mna大鼠）中观察到血清PCSK 9和胆固醇水平显著升高。在两种模型中，当肝脏表达降低时，肾脏中PCSK 9的表达增加。接下来研究CCD中PCSK 9减少或增加对肾病综合征中高胆固醇血症的影响。在集合管中PCSK 9表达选择性缺陷的小鼠在注射肾毒性血清后没有发生高胆固醇血症。在Rrm 2b −/−小鼠中，用阿米洛利阻断上皮钠通道活性导致CCD中其伴侣蛋白PCSK 9的表达增加，随后血浆水平升高，高胆固醇血症恶化。因此，我们的数据表明，肾脏中的PCSK 9在肾病综合征高胆固醇血症的发生中起作用，并为肾病综合征患者早期消耗PCSK 9以预防高胆固醇血症的发生提供了依据。
The proprotein PCSK9 functions as a chaperone for the epithelial sodium channel in the cortical collecting duct (CCD), is highly expressed in the liver, and plays a significant role in the pathogenesis of hypercholesterolemia. Lower levels of PCSK9 expression also occur in the normal kidney and intestine. Here, we found increased PCSK9 expression in the CCD of biopsies of patients with primary glomerular disease and explored a possible relationship with hypercholesterolemia of nephrotic syndrome. Significantly elevated serum PCSK9 and cholesterol levels were noted in two models of focal and segmental glomerulosclerosis, the Rrm2b−/− mouse and the Buffalo/Mna rat. Increased expression of PCSK9 in the kidney occurred when liver expression was reduced in both models. The impact of reduced or increased PCSK9 in the CCD on hypercholesterolemia in nephrotic syndrome was next studied. Mice with selective deficiency of PCSK9 expression in the collecting duct failed to develop hypercholesterolemia after injection of nephrotoxic serum. Blocking epithelial sodium channel activity with Amiloride in Rrm2b−/− mice resulted in increased expression of its chaperone PCSK9 in the CCD, followed by elevated plasma levels and worsening hypercholesterolemia. Thus, our data suggest that PCSK9 in the kidney plays a role in the initiation of hypercholesterolemia in nephrotic syndrome and make a case for depletion of PCSK9 early in patients with nephrotic syndrome to prevent the development of hypercholesterolemia.
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影响因子：
37.8
作者：
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