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

为了探讨具有强大利尿和血管松弛作用的利钠肽在组织损伤和重塑中的作用，我们采用不同的肾病模型研究了转基因小鼠慢性过量的脑利钠肽(BNP)对肾脏损伤的影响。在抗肾小球基底膜抗体肾小球肾炎(GN)模型中，对照组小鼠在8-12周出现进展性GN并伴有严重的蛋白尿(是基线水平的21倍)和严重的肾小球/肾小管间质损害。相比之下，BNP转基因小鼠(BNP-TG)只表现出轻微的一过性蛋白尿，没有明显的组织损伤。在单侧输尿管梗阻肾纤维化模型中，肾组织中转化生长因子β和单核细胞趋化蛋白-1的基因表达以及ERK/MAP激酶的激活均显著降低，提示这些因素共同作用可减轻肾损伤。在单侧输尿管梗阻的肾纤维化模型中，间质…与对照组非转基因小鼠相比，BNP-TG组小鼠的肝纤维化程度明显改善。转化生长因子-β的表达在BNP-TG组明显降低。随后的分析表明，在BNP-TG中，肾小管周围毛细血管中的血FBW显著保持，表明这种血管保护机制可能阻止纤维化过程的进展。在糖尿病肾病模型中，对照组小鼠在链脲佐菌素诱导的糖尿病发作16周后出现显著的蛋白尿和肌膜扩张。BNP-TG组的这些变化明显较轻。这些结果表明，利钠肽可能通过拮抗转化生长因子-β和单核细胞趋化蛋白-1等致纤维化刺激而发挥肾脏保护作用。提示利钠肽系统的激活可能较少适用于各种肾病的临床应用。

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