Protective Role of the Natriuretic Peptide System in Tissue Injury and Remodeling

为了探讨具有强利尿和血管舒张特性的利钠肽在组织损伤和重塑中的作用，我们采用多种肾病模型研究了脑利钠肽（BNP）在转基因小鼠中慢性过量对肾损伤的影响。对照非转基因小鼠在8-12周时发展为进行性GN，伴有严重的高蛋白尿（基线水平的21倍）和严重的肾小球/肾小管间质损伤。相反，BNP转基因小鼠（BNP-Tg）仅表现出轻微和短暂的蛋白尿，没有明显的组织损伤。BNP-Tg组肾组织中转化生长因子β（TGF-β）和单核细胞趋化蛋白1（MCP-1）的基因表达以及ERK/MAP激酶的活化明显降低，提示它们共同作用减轻肾损伤。 ...更多信息 与对照非转基因小鼠相比，BNP-Tg中的纤维化显著改善。BNP-Tg组TGF-β表达明显降低。随后的分析显示，在BNP-Tg中，肾管周毛细血管中的血液fbw显著维持，这表明这种血管保护机制可能对纤维化过程的进展起作用。在糖尿病肾病模型中，对照小鼠在链脲佐菌素诱导的糖尿病发作后16周出现显著的蛋白尿伴肾小球扩张。这些变化在BNP-Tg中明显较轻。BNP在体内和体外均能抑制系膜TGF-β的上调，提示这可能是一种共同的肾脏保护机制。这些结果表明，利钠肽可能通过对抗TGF-β和MCP-1等纤维化刺激物而发挥肾脏保护作用，提示利钠肽系统的激活应可用于临床治疗各种肾病。

In prder to explore the rote of natriuretic peptides, with potent diuretic and vasorelaxing properties, in tissue injury and remodeling, we investigated the effect of chronic excess of brain natriuretic peptide (BNP) in transgenic mice on renal injuries using various nephropathy modelsIn a model of anti-glomerular-basement-membrane antibody glomerulonephritis (GN), control nontransgenic mice developed progressive GN with heavy prateinuria (21 times of baseline level) and severe glomerular/tubulointerstitial damage at 8-12 weeks. In contrast, BNP-transgenic mice (BNP-Tg) showed only minor and transient proteinuria with no apparent tissue damage. Gene expression of transforming growth factorβ (TGF-β) and monocyte chemoattractant protein-1 (MCP-1) as well as the activation of ERK/MAP kinase within renal tissues was much reduced in BNP-Tg, suggesting that these worked together to ameliorate renal injuriesIn a model of renal fibrosis with unilateral ureteral obstruction (UUO), interstitial … More fibrosis was significantly ameliorated in BNP-Tg as compared with control nontransgenic mice. TGF-β expresstan was much reduced in BNP-Tg. Subsequent analysis revealed that the blood fbw in the renal peritubular capillary was significantly maintained in BNP-Tg, suggesting that such mechanisms of vascular protection may act against the progression of fibrotic processesIn a model of diabetic nephropathy, control mice developed significant proteinuria with masangial expansion 16 weeks after the onset of streptozotocin-induced diabetes. These changes were significantly milder in BNP-Tg. BNP inhibited the mesangial up regulation of TGF-β in vivo and in vitro, suggesting that this may provide a common key mechanism of renoprotectionThese results indicate that natriuretic peptides potentially exert renoprotective effects by counteracting the fibrogenic stimuli such as TGF-βand MCP-1, suggesting that the activation of the natriuretic peptide system should be clinically applicable against various nephropathies Less