title: A mouse model of Townes-Brocks syndrome expressing a truncated mutant Sall1 protein is protected from acute kidney injury.
abstract: 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.
authors: 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;
authors: Sara
authors: S
authors: Hirsch
authors: Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors: Tarek
authors: T
authors: El-Achkar
authors: Department of Internal Medicine (Nephrology), Saint Louis University, St. Louis, Missouri; John Cochran Division, Veterans Affairs St. Louis Health Care System, St. Louis, Missouri;
authors: Lynn
authors: L
authors: Robbins
authors: Department of Internal Medicine (Nephrology), Saint Louis University, St. Louis, Missouri; John Cochran Division, Veterans Affairs St. Louis Health Care System, St. Louis, Missouri;
authors: Jeannine
authors: J
authors: Basta
authors: Department of Internal Medicine (Nephrology), Saint Louis University, St. Louis, Missouri;
authors: Monique
authors: M
authors: Heitmeier
authors: Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors: Ryuichi
authors: R
authors: Nishinakamura
authors: Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, Missouri; Department of Internal Medicine (Nephrology), Saint Louis University, St. Louis, Missouri; John Cochran Division, Veterans Affairs St. Louis Health Care System, St. Louis, Missouri; rauchman@slu.edu.
authors: Michael
authors: M
authors: Rauchman
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism*; D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001006:Anus, Imperforate / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D013933:Thumb / Q000002:abnormalities*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; C491254:Sall1 protein, mouse; D014157:Transcription Factors; D051547:Heme Oxygenase-1
keywords: Sall1; Townes-Brocks syndrome; acute kidney injury; nephrotoxicity; renal hypoplasia