Dept. of Biochemistry, Teikyo Univ. School of Medicine, Itabashi, Tokyo, Japan.
Am J Physiol Renal Physiol. 2012 Oct;303(7):F1049-59. doi: 10.1152/ajprenal.00047.2012. Epub 2012 Jul 25.
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∼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.
Saposin D 缺陷（Sap-D(-/-)）小鼠由于肾功能衰竭伴严重肾积水而出现多尿和多饮，并过早死亡。这些症状出现在它们大约 3 个月大的时候。为了研究它们水代谢紊乱的发病机制，我们试图限制水的供应，并观察生理和生化参数的连续变化。我们还在几个时间点分析了肾脏的组织学变化。在 3 个月大、开始限制水供应之前，它们的基础精氨酸加压素水平与野生型（WT）相当。24 小时禁水和去氨基精氨酸加压素给药在一定程度上改善了多饮和多尿。然而，Sap-D(-/-)小鼠的肌酐浓度明显高于 WT 小鼠，这表明在这个年龄，受影响的小鼠已经出现了一些肾功能损害。肾脏组织学分析显示，肾小管和集合管在 3 个月后扩张。6 个月后，观察到空泡形成，大量炎性细胞迁移到导管周围，管状起源的上皮单层细胞被各种大小的丰富囊肿所取代。10∼12 个月大时，出现严重的囊性畸形。另一方面，从 4 个月大开始的 8 个月的水限制显著改善了管状损伤，并将一度减弱的管状水通道蛋白 2 蛋白的量恢复到 WT 水平。此外，10 个月的水限制改善了它们的肾功能。值得注意的是，此后继续进行水限制，使总生存时间与 WT 相当。总之，多尿、严重的肾小管损伤和肾衰竭通过仅仅 10 个月的水限制得到改善，如果这种疾病不是由原发性多尿以外的任何过程引起的，那么这种水限制会引发致命的脱水。我们的研究表明，长期的水限制肯定会改善肾脏的组织病理学变化，从而预防 Sap-D(-/-)小鼠的过早死亡。
