Role of humoral factors in the development and progression of metabolic syndrome-related kidney diseases

代谢综合征（MetS）表现为体液或内分泌因素的调节受损，如肾素-血管紧张素-醛固酮系统的增强。我们研究了体液因子在met相关性肾损伤中的作用。利钠肽（ANP和BNP）受体GC-A在肾小管中大量表达，但其在肾小球损伤中的作用尚不清楚。当GC-A基因敲除小鼠受到醛固酮和高盐刺激时，观察到大量蛋白尿和明显的足细胞损伤，ARB、抗氧化剂或p38 MAPK抑制剂可以减轻这种损伤，这表明它们具有治疗潜力。在伴有血脂异常的糖尿病小鼠模型中，我们发现与稳态炎症相关的TLR4及其配体MRP8显著上调，同时肾病恶化。tlr4缺陷小鼠的肾损伤明显减轻。MRP8在晚期人类糖尿病肾病中的表达也增强，提示其作为预后标志物的作用。

Metabolic syndrome (MetS) represents impaired regulation of humoral or endocrine factors, such as the enhanced renin-angiotensin-aldosterone system. We investigated roles of humoral factors in MetS-associated renal injury.The natriuretic peptide (ANP and BNP) receptor GC-A is abundantly expressed in renal tubules, but its role in glomerular injury is unknown. When GC-A knockout mice were subjected to aldosterone and high salt, massive proteinuria with marked podocyte injury was observed, which was alleviated with an ARB, antioxidant, or p38 MAPK inhibitor, suggesting their therapeutic potential.In mouse models of diabetes with dyslipidemia, we found that TLR4 and its ligand MRP8, factors associated with homeostatic inflammation, were markedly upregulated together with worsening of nephropathy. Renal injury was significantly alleviated in TLR4-deficient mice. Expression of MRP8 was also enhanced in advanced human diabetic nephropathy, suggesting its role as a prognostic marker.