Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice
Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice
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DOI：
10.1007/s00125-006-0352-y
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发表时间：
2006-10-01
期刊：
影响因子：
8.2
通讯作者：
Nakao, K.
中科院分区：
文献类型：
--
作者：
Makino, H.;Mukoyama, M.;Nakao, K.
脑利钠肽（BNP）是一种强有力的血管舒张和利钠肽，由心脏分泌，具有心脏保护作用。我们先前已经产生了过度分泌的转基因小鼠（BNP-Tg小鼠），其在肝脏中过量产生BNP，BNP被释放到循环中。使用该动物模型，我们成功地证明了肾消融术后和增殖性肾小球肾炎中肾损伤的改善。肾小球高滤过是一种早期血液动力学紊乱，是糖尿病肾病发病的重要机制之一。本研究的目的是探讨内源性利钠肽在糖尿病肾病发生、发展中的作用。我们评价了链脲佐菌素诱导的BNP-Tg糖尿病小鼠肾损伤和纤维化的进展。我们还研究了BNP对高糖诱导的肾小球系膜细胞信号异常的影响。诱导糖尿病后，对照小鼠表现出尿白蛋白排泄逐渐增加，肾功能受损，而这些变化在BNP-Tg小鼠中显着改善。值得注意的是，糖尿病BNP-Tg小鼠表现出最小的系膜纤维化，几乎没有肾小球肥大。在糖尿病BNP-Tg小鼠中，肾小球细胞外信号调节激酶、TGF-β和细胞外基质蛋白的上调也被显著抑制。在培养的肾小球系膜细胞中，在高糖下上述级联的激活被加入BNP所废除。BNP的慢性过量可防止糖尿病背景下的肾小球损伤，这表明利钠肽的肾脏保护作用可能在治疗上适用于预防糖尿病肾病的进展。
Brain natriuretic peptide (BNP) is a potent vasorelaxing and natriuretic peptide that is secreted from the heart and has cardioprotective properties. We have previously generated hypotensive transgenic mice (BNP-Tg mice) that overproduce BNP in the liver, which is released into the circulation. Using this animal model, we successfully demonstrated the amelioration of renal injury after renal ablation and in proliferative glomerulonephritis. Glomerular hyperfiltration is an early haemodynamic derangement, representing one of the key mechanisms of the pathogenesis of diabetic nephropathy. Based on the suggested involvement of increased endogenous natriuretic peptides, the aim of this study was to investigate their role in the development and progression of diabetic nephropathy.We evaluated the progression of renal injury and fibrogenesis in BNP-Tg mice with diabetes induced by streptozotocin. We also investigated the effect of BNP on high glucose-induced signalling abnormalities in mesangial cells.After induction of diabetes, control mice exhibited progressively increased urinary albumin excretion with impaired renal function, whereas these changes were significantly ameliorated in BNP-Tg mice. Notably, diabetic BNP-Tg mice revealed minimal mesangial fibrogenesis with virtually no glomerular hypertrophy. Glomerular upregulation of extracellular signal-regulated kinase, TGF-beta and extracellular matrix proteins was also significantly inhibited in diabetic BNP-Tg mice. In cultured mesangial cells, activation of the above cascade under high glucose was abrogated by the addition of BNP.Chronic excess of BNP prevents glomerular injury in the setting of diabetes, suggesting that renoprotective effects of natriuretic peptides may be therapeutically applicable in preventing the progression of diabetic nephropathy.