Hirsch Sara, El-Achkar Tarek, Robbins Lynn, Basta Jeannine, Heitmeier Monique, Nishinakamura Ryuichi, Rauchman Michael
Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, Missouri; John Cochran Division, Veterans Affairs St. Louis Health Care System, St. Louis, Missouri;
Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana; and.
Am J Physiol Renal Physiol. 2015 Nov 15;309(10):F852-63. doi: 10.1152/ajprenal.00222.2015. Epub 2015 Aug 26.
It has been postulated that developmental pathways are reutilized during repair and regeneration after injury, but functional analysis of many genes required for kidney formation has not been performed in the adult organ. Mutations in SALL1 cause Townes-Brocks syndrome (TBS) and nonsyndromic congenital anomalies of the kidney and urinary tract, both of which lead to childhood kidney failure. Sall1 is a transcriptional regulator that is expressed in renal progenitor cells and developing nephrons in the embryo. However, its role in the adult kidney has not been investigated. Using a mouse model of TBS (Sall1TBS), we investigated the role of Sall1 in response to acute kidney injury. Our studies revealed that Sall1 is expressed in terminally differentiated renal epithelia, including the S3 segment of the proximal tubule, in the mature kidney. Sall1TBS mice exhibited significant protection from ischemia-reperfusion injury and aristolochic acid-induced nephrotoxicity. This protection from acute injury is seen despite the presence of slowly progressive chronic kidney disease in Sall1TBS mice. Mice containing null alleles of Sall1 are not protected from acute kidney injury, indicating that expression of a truncated mutant protein from the Sall1TBS allele, while causative of congenital anomalies, protects the adult kidney from injury. Our studies further revealed that basal levels of the preconditioning factor heme oxygenase-1 are elevated in Sall1TBS kidneys, suggesting a mechanism for the relative resistance to injury in this model. Together, these studies establish a functional role for Sall1 in the response of the adult kidney to acute injury.
据推测，发育途径在损伤后的修复和再生过程中会被重新利用，但许多肾脏形成所需基因的功能分析尚未在成体器官中进行。SALL1基因的突变会导致汤姆斯-布罗克斯综合征（TBS）以及非综合征性先天性肾脏和尿路异常，这两种情况都会导致儿童肾衰竭。Sall1是一种转录调节因子，在胚胎期的肾祖细胞和发育中的肾单位中表达。然而，其在成体肾脏中的作用尚未得到研究。我们使用TBS小鼠模型（Sall1TBS），研究了Sall1在急性肾损伤反应中的作用。我们的研究表明，在成熟肾脏中，Sall1在终末分化的肾上皮细胞中表达，包括近端小管的S3段。Sall1TBS小鼠对缺血再灌注损伤和马兜铃酸诱导的肾毒性表现出显著的保护作用。尽管Sall1TBS小鼠存在缓慢进展的慢性肾病，但仍能观察到这种对急性损伤的保护作用。携带Sall1无效等位基因的小鼠对急性肾损伤没有保护作用，这表明来自Sall1TBS等位基因的截短突变蛋白的表达虽然会导致先天性异常，但却能保护成体肾脏免受损伤。我们的研究进一步表明，Sall1TBS肾脏中预处理因子血红素加氧酶-1的基础水平升高，这提示了该模型中相对抗损伤的一种机制。总之，这些研究确定了Sall1在成体肾脏对急性损伤反应中的功能作用。
