Epidermal growth factor deficiency predisposes to progressive renal disease.
Epidermal growth factor deficiency predisposes to progressive renal disease.
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DOI：
10.1096/fj.202101837r
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发表时间：
2022-05
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表皮生长因子（EGF）是由肾脏中的粗升支（TAL）和远曲小管（DCT）产生的。尿EGF水平降低与慢性肾脏疾病有关，但尚不清楚EGF的生理水平是否能保护肾脏免受进行性肾脏疾病的影响。在这里，我们发现，混合遗传背景的EGF缺陷型小鼠尿微量白蛋白增加，这些小鼠的一个子集发展为严重的进行性肾脏疾病伴氮质血症，这在具有这种混合遗传背景的WT或TGFα缺陷型同窝小鼠中未见。这些氮质血症EGF缺陷小鼠发生新月体肾小球肾炎，与肾小球中的HB-EGF/EGFR过度活化相关，以及与肾β-catenin/mTOR过度活化相关的近端小管刷状缘衰减、DCT扩张和肾纤维化。仅在EGF缺陷小鼠的一个子集中观察到这些严重的肾脏病理表明，株特异性修饰等位基因的独立分离有助于仅在缺乏EGF时表现出的肾脏异常的严重性。这些发现将缺乏EGF与成年哺乳动物肾脏中的肾脏病理联系起来，支持生理水平的EGF对维持肾小球、PT和DCT功能的作用。这些观察结果表明，减少EGF水平使肾脏易患进行性肾脏疾病。
Epidermal growth factor (EGF) is produced in the kidney by thick ascending limbs (TALs) and distal convoluted tubules (DCTs). Reduced urinary EGF levels have been associated with chronic kidney disease but it is not known whether physiological levels of EGF protect the kidney from progressive renal disease. Here, we show that EGF-deficient mice on a mixed genetic background had increased urinary microalbumin, and a subset of these mice developed severe progressive renal disease with azotemia that was not seen in WT or TGFα-deficient littermates with this mixed genetic background. These azotemic EGF-deficient mice developed crescentic glomerulonephritis linked to HB-EGF/EGFR hyperactivation in glomeruli, as well as attenuation of the proximal tubule brush border, DCT dilatation, and kidney fibrosis associated with renal β-catenin/mTOR hyperactivation. The observation of these severe renal pathologies only in a subset of EGF-deficient mice suggests that independent segregation of strain-specific modifier alleles contributes to the severity of the renal abnormalities that only manifest when EGF is lacking. These findings link the lack of EGF to renal pathologies in the adult mammalian kidney, in support of a role of physiological levels of EGF for maintaining the function of glomeruli, PTs, and DCTs. These observations suggest that diminished EGF levels predispose kidneys to progressive renal disease.