Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Am J Physiol Renal Physiol. 2011 Mar;300(3):F792-800. doi: 10.1152/ajprenal.00570.2010. Epub 2010 Dec 22.
Urine outflow obstruction activates a variety of profibrotic factors, including the intrarenal renin-angiotensin system. However, the obstruction also nullifies the transmural hydraulic pressure difference across the glomerular capillary wall, an established inducer of glomerulosclerosis. In the present study, we investigated whether, and by what mechanism, urine outflow obstruction affects the process of progressive glomerulosclerosis. For this purpose, we tested the effect of unilateral ureteral obstruction (UUO) of 7 days duration in two distinct mouse models of glomerulosclerosis. In the human immunodeficiency virus (HIV) nephropathy model, where HIV-1 genes are selectively expressed in podocytes and develop progressive podocyte damage and glomerulosclerosis, UUO protected against sclerosis with preservation of podocytes morphologically and immunohistochemically. In contrast, the nonobstructed contralateral kidneys of these mice, as well as sham-operated HIV-1 mouse kidneys, developed severe podocyte injury and glomerulosclerosis. The protection against glomerulosclerosis imparted by ureteral obstruction was also documented in the NEP25 model of podocyte injury, in which a single injection of immunotoxin, LMB2, triggers selective podocyte injury followed by glomerulosclerosis, both of which were protected by UUO. Notably, intervention with an angiotensin II type 1 receptor antagonist provided only a partial protective effect in each of the models. These results demonstrate that urine outflow obstruction protects the glomerulus from progressive sclerosis. The results further reveal that this protection occurs at a very early stage of the pathologic process, namely, damage of podocytes.
尿流梗阻会激活多种促纤维化因子，包括肾内肾素-血管紧张素系统。然而，梗阻也消除了穿过肾小球毛细血管壁的跨壁液压差，这是肾小球硬化的一个既定诱导因素。在本研究中，我们研究了尿流梗阻是否以及通过何种机制影响进行性肾小球硬化的过程。为此，我们在两种不同的肾小球硬化小鼠模型中测试了单侧输尿管梗阻（UUO）7 天的效果。在人类免疫缺陷病毒（HIV）肾病模型中，HIV-1 基因选择性表达于足细胞，并导致进行性足细胞损伤和肾小球硬化，UUO 可防止硬化，足细胞形态和免疫组化均得以保留。相比之下，这些小鼠的未梗阻对侧肾脏以及假手术的 HIV-1 小鼠肾脏则发生严重的足细胞损伤和肾小球硬化。UUO 还可预防足细胞损伤的 NEP25 模型中的肾小球硬化，其中单次注射免疫毒素 LMB2 可引发选择性足细胞损伤，随后发生肾小球硬化，UUO 均可预防这两种情况。值得注意的是，血管紧张素 II 型 1 型受体拮抗剂的干预在每种模型中仅提供部分保护作用。这些结果表明，尿流梗阻可保护肾小球免受进行性硬化。结果还表明，这种保护发生在病理过程的非常早期阶段，即足细胞损伤。
