Dissecting the genetic basis of kidney tubule response to hyperoxaluria using chromosome substitution strains
Dissecting the genetic basis of kidney tubule response to hyperoxaluria using chromosome substitution strains
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DOI：
10.1152/ajprenal.00009.2009
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发表时间：
2009-08-01
影响因子：
4.2
通讯作者：
Mandel, Neil S.
中科院分区：
文献类型：
--
作者：
Wiessner, John H.;Garrett, Michael R.;Mandel, Neil S.
Wiessner JH，加勒特MR，Roman RJ，Mandel NS.用染色体置换菌株剖析肾小管对高尿酸反应的遗传基础。美国肾脏生理学杂志297：F301-F306，2009年。首次发表于2009年6月3日; doi：10.1152/ajprenal.00009.2009。遗传学是否可能在肾小管对草酸盐暴露的病理生理反应中起作用仍然没有被探索，尽管有多达15%的美国研究表明。S.人们每年都会出现由草酸钙组成的肾结石。为了探讨这个问题，我们利用了一组染色体置换菌株，其中一个染色体在一个时间从布朗挪威（BN）大鼠转移到达尔盐敏感（SS）的遗传背景。通过在饮水中添加羟脯氨酸（HP）诱导高尿酸血症。一项剂量反应（0-2% HP）研究发现，随着HP浓度增加，SS和BN均显示出相同水平的草酸盐排泄，但只有BN显示出尿路上皮病理学变化，并显示尿路上皮损伤部位的晶体沉积与剂量（1.5-2.0%）相关。用2.0% HP处理经济组，并评价高尿酸、肾损伤和晶体沉积。抗性SS和SS-4、-6、-7、-8、-9、-11、-16和-20（BN）经济大鼠之间的肾小管损伤（面积%）和晶体沉积（面积%）相似。然而，与SS亲本相比，SS-2（BN）中的肾小管损伤显著增加（分别为9.8 +/- 1.56和4.2 +/-1.09%）。在SS-2（BN）和SS-18（BN）中观察到晶体沉积（分别为4.7 +/- 0.70和3.5 +/-1.3%），其程度与敏感BN（3.2 +/- 0.44%）相同。与SS-2（BN）中观察到的更严重的广泛肾小管损伤相比，SS-18（BN）中观察到晶体沉积而没有广泛的整体肾小管损伤，这一事实表明每个位点的潜在机制是不同的。总之，这些研究确定BN大鼠表现出草酸盐相关的病理学，并且它们保留了与尿路上皮损伤一致的草酸钙晶体，但SS大鼠没有。这些观察结果表明，BN大鼠2号和18号染色体上的基因有助于这些过程。
Wiessner JH, Garrett MR, Roman RJ, Mandel NS. Dissecting the genetic basis of kidney tubule response to hyperoxaluria using chromosome substitution strains. Am J Physiol Renal Physiol 297: F301-F306, 2009. First published June 3, 2009; doi:10.1152/ajprenal.00009.2009.-Whether genetics may play a role in the pathophysiologic response of kidney tubules to oxalate exposure remains unexplored despite that as many as 15% of the U. S. population annually will experience a kidney stone composed of calcium oxalate. To explore this issue, we utilized a panel of chromosome substitution strains in which one chromosome at a time was transferred from the Brown Norway (BN) rat onto the Dahl salt-sensitive (SS) genetic background. Hyperoxaluria was induced by adding hydroxyproline (HP) to the drinking water. A dose-response (0-2% HP) study found that both SS and BN exhibited the same level of oxalate excretion as HP concentration increased, but only the BN exhibited changes in urothelial pathology and demonstrated crystal deposition at sites of urothelial injury as a function of dose (at 1.5-2.0%). The consomic panel was treated with 2.0% HP and evaluated for hyperoxaluria, renal injury, and crystal deposition. Tubular injury (% Area) and crystal deposition (% Area) were similar between the resistant SS and SS-4, -6, -7, -8, -9, -11, -16, and -20(BN) consomic rats. However, tubular injury was significantly increased in SS-2(BN) compared with the SS parental (9.8 +/- 1.56 and 4.2 +/- 1.09%, respectively). Crystal deposition was observed in SS-2(BN) and SS-18(BN) (4.7 +/- 0.70 and 3.5 +/- 1.3%, respectively) to the same extent as seen in the susceptible BN (3.2 +/- 0.44%). The fact that crystal deposition was observed in SS-18(BN) without extensive overall tubule injury, compared with the more severe widespread tubular injury seen in SS-2(BN), suggests that the underlying mechanism of each locus is different. In conclusion, these studies establish that BN rats demonstrate oxalate-associated pathology and they retain calcium oxalate crystals coincident with urothelial injury but SS rats do not. These observations establish that BN rat chromosome 2 and 18 harbor genes that contribute to these processes.