Uromodulin and Inflammation in Neonatal Obstructive Nephropathy

先天性梗阻性肾病是婴幼儿肾功能衰竭的主要原因。肾功能不全是由于发育中的肾脏发育和成熟受阻所致。先天性梗阻性肾病导致肾小管细胞凋亡、肾小管萎缩和间质纤维化。这些事件的核心是细胞因子介导的巨噬细胞流入梗阻的肾脏。单侧输尿管梗阻后巨噬细胞释放趋化因子、促炎和促纤维化细胞因子以及活性氧。它们激活成纤维细胞，促进肾小管间质损伤的发展。尿调蛋白是一种肾脏特异性蛋白质，由Henle环的粗大升支(TAL)细胞产生。尿调蛋白的表达随着TAL节段的成熟而稳步增加，在胎儿和新生儿生活中达到最高水平。尿调蛋白在生理条件下的作用是肾脏保护作用。相比之下，在病理条件下，尿调蛋白可以激活炎症细胞，引发肾小管间质损伤。尿调蛋白的这种促炎作用似乎是由单核细胞和巨噬细胞介导的。抗炎信号通路也影响UUO后的肾脏转归。巨噬细胞和肾小管上皮细胞分泌的白介素37(IL-37)是炎症反应的天然抑制因子。IL-37的表达几乎完全抑制了促炎细胞因子。白介素10(IL-10)是另一种重要的免疫抑制细胞因子。IL-10限制免疫反应，防止免疫介导的组织损伤和纤维化。到目前为止，尿调蛋白、IL-37和IL-10对UUO新生小鼠巨噬细胞浸润和肾小管间质损伤的研究尚未见报道。了解梗阻新生儿肾脏的促炎和抗炎信号的过程将有助于改进治疗策略，并有助于限制肾功能不全的进展。

Congenital obstructive nephropathy is the main cause of renal failure in infants and children. Renal insufficiency is due to impaired growth and maturation in the developing kidney with obstruction. Congenital obstructive nephropathy leads to tubular apoptosis, tubular atrophy, and interstitial fibrosis. Central to these events is the cytokine-mediated influx of macrophages into the obstructed kidney. Macrophages release chemokines, proinflammatory and profibrotic cytokines, and reactive oxygen species following unilateral ureteral obstruction. They activate fibroblasts and contribute to the development of tubulointerstitial injury. Uromodulin is a kidney-specific protein produced by cells of the thick ascending limb (TAL) of the loop of Henle. Uromodulin expression steadily increases with the maturation of the TAL segments, reaching a maximal level in fetal and neonatal life. The function of uromodulin under physiologic conditions is renoprotective. By contrast, under pathologic conditions uromodulin can activate inflammatory cells and trigger tubulointerstitial damage. This proinflammatory role of uromodulin seems to be mediated by monocytes and macrophages. Anti-inflammatory signaling pathways also influence the renal outcome after UUO. Interleukin-37 (IL-37) released by macrophages and tubular cells is natural inhibitor of inflammatory responses. Expression of IL-37 induces near complete suppression of proinflammatory cytokines. Interleukin-10 (IL-10) is another key immunosuppressive cytokine. IL-10 limits immune responses and protects from immune-mediated tissue damage and fibrosis. So far, uromodulin, IL-37, and IL-10 have not been studied for macrophage infiltration and tubulointerstitial injury following UUO in neonatal mice. Understanding the process of pro- and anti-inflammatory signaling in the neonatal kidney with obstruction will improve therapeutical strategies and help to limit the progression of renal insufficiency.