Primary polydipsia, but not accumulated ceramide, causes lethal renal damage in saposin D-deficient mice
Primary polydipsia, but not accumulated ceramide, causes lethal renal damage in saposin D-deficient mice
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DOI：
10.1152/ajprenal.00047.2012
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发表时间：
2012-10-01
影响因子：
4.2
通讯作者：
Okazaki, Tomoki
中科院分区：
文献类型：
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作者：
Hisaki, Harumi;Matsuda, Junko;Okazaki, Tomoki
[10]张文忠，张文忠.原发性烦渴，而不是累积的神经酰胺，导致saposin D缺陷小鼠致命的肾损伤。美国肾脏生理学杂志303：F1049-F1059，2012年。首次发表于2012年7月25日; doi：10.1152/ajprenal.00047.2012.- Saposin D缺陷（Sap-D-/-）小鼠出现多饮/多尿，并因肾衰竭伴严重肾积水而过早死亡。这些症状出现在他们大约3个月大的时候。为了探讨其水处理不当的发病机制，我们试图限制供水，并跟踪生理和生化参数的顺序变化。我们还分析了几个时间点的肾脏组织学变化。在3月龄时，就在开始限水挑战之前，他们的基线精氨酸加压素水平与野生型（WT）水平相当。24小时禁水和给予脱氨基D-精氨酸加压素在一定程度上改善了多饮和多尿。然而，Sap-D-/-小鼠的肌酐浓度显著高于WT小鼠，表明在该年龄段受影响的小鼠中已经出现了一些肾损伤。肾组织学分析显示，肾小管和集合管扩张后3月龄。6月龄时，可见空泡形成，许多炎性细胞向导管周围迁移，管状上皮单层细胞被大量大小不等的囊肿所取代。在10 ~ 12月龄时，出现严重的囊性畸形。另一方面，从4月龄开始的8个月长的水限制显著改善了肾小管损伤，并将一度被抑制的肾小管水通道蛋白2的量恢复到WT水平。此外，10个月的水限制改善他们的肾功能。值得注意的是，通过此后持续限水，总生存期变得与WT相当。总之，多尿、破坏性肾小管病变和肾功能衰竭通过仅仅10个月的限水得到改善，如果疾病是由原发性多饮以外的任何过程引起的，则会引发致命的脱水。我们的研究表明，长期限水确实改善了Sap-D-/-小鼠的肾脏组织病理学变化，从而预防了过早死亡。
Hisaki H, Matsuda J, Tadano-Aritomi K, Uchida S, Okinaga H, Miyagawa M, Tamamori-Adachi M, Iizuka M, Okazaki T. Primary polydipsia, but not accumulated ceramide, causes lethal renal damage in saposin D-deficient mice. Am J Physiol Renal Physiol 303: F1049-F1059, 2012. First published July 25, 2012; doi:10.1152/ajprenal.00047.2012.-Saposin D-deficient (Sap-D-/-) mice develop polydipsia/polyuria and die prematurely due to renal failure with robust hydronephrosis. Such symptoms emerged when they were around 3 mo of age. To investigate the pathogenesis of their water mishandling, we attempted to limit water supply and followed sequential changes of physiological and biochemical parameters. We also analyzed renal histological changes at several time points. At 3 mo old just before water restriction challenge was started, their baseline arginine vasopressin level was comparable to the wild-type (WT) level. Twenty-four-hour water deprivation and desamino D-arginine vasopressin administration improved polydipsia and polyuria to certain degrees. However, creatinine concentrations in Sap-D-/- mice were significantly higher than those in WT mice, suggesting that some renal impairment already emerged in the affected mice at this age. Renal histological analyses revealed that renal tubules and collecting ducts were expanded after 3 mo old. After 6 mo old, vacuolar formation was observed, many inflammatory cells migrated around the ducts, and epithelial monolayer cells of tubular origin were replaced by plentiful cysts of various sizes. At 10 similar to 12 mo old, severe cystic deformity appeared. On the other hand, 8-mo-long water restriction started at 4 mo old dramatically improved tubular damage and restored once-dampened amount of tubular aquaporin2 protein to the WT level. Furthermore, 10-mo-long water restriction ameliorated their renal function. Remarkably, by continuing water restriction thereafter, overall survival period became comparable with that of the WT. Together, polyuria, devastating renal tubular lesions, and renal failure were ameliorated by the mere 10-mo-long water restriction, which would trigger lethal dehydration if the disease were to be caused by any processes other than primary polydipsia. Our study demonstrates that long-term water restriction surely improved renal histopathological changes leading to prevention of premature death in Sap-D-/- mice.