Research press release


Nature Medicine

A new player in kidney disease


有足細胞(糸球体上皮細胞)は腎臓にある血液濾過に不可欠な細胞で、この細胞の機能が異常を来すと腎臓がうまく働かないネフローゼ症候群につながり、大量のタンパク質が血中から尿中へと漏出する。S Chughたちは、有足細胞からのAngpyl4の分泌亢進がこの状況を引き起こすことを明らかにした。実験的にネフローゼ症候群を発症させたラットの有足細胞では、Angptl4 mRNAとAngptl4タンパク質のレベルが非常に高くなっていることがわかり、ある種のネフローゼ症候群患者の生検でも同様だった。また、マウスとラットの有足細胞で導入したAngptl4遺伝子を過剰に発現させるだけで、ネフローゼ症候群を引き起こすに十分なことと、マウスでAngptl4遺伝子をノックアウトするとネフローゼ症候群を起こさなくなることもわかった。


The secreted glycoprotein angiopoietin-like-4 (Angptl4) is shown to play a role in kidney disease in a study in this week’s Nature Medicine. The results suggest a possible therapeutic avenue for some forms of kidney damage.

Dysfunction of podocytes ― critical cells within the kidney involved in filtration of the blood ― can lead to nephrotic syndrome in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine. Sumant Chugh and his colleagues show that hypersecretion of Angptl4 by podocytes results in this condition. The team found that Angptl4 mRNA and protein are highly upregulated in the podocytes of rats experimentally induced to have nephrotic syndrome, as well as in human biopsies from patients with a form of it. They also showed that transgenic overexpression of Angptl4 in podocytes in mice and in rats is sufficient to induce nephrotic syndrome, while Angptl4 knockout in mice showed protection from the disorder.

How overexpression of Angptl4 leads to nephrotic syndrome is not entirely clear, but the team found that much of the hypersecreted Angptl4 is not properly post-translationally modified by glycosylation. This results in a change of charge of the protein, which in turn could change the net charge of the extracellular matrix in the filtration units of the kidney, leading to its dysfunction. Supporting this hypothesis the group found that feeding a sialic acid precursor to the rats overexpressing Angptl4 in podocytes vastly increased the pool of secreted Angptl4 with a normal charge and helped ameliorate their kidney disease.

doi: 10.1038/nm.2261


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