A mouse model of Townes-Brocks syndrome expressing a truncated mutant Salll protein is protected from acute kidney injury

摘要

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 SALLI cause Townes-Brocks syndrome (TBS) and nonsyndromic congenital anomalies of the kidney and urinary tract, both of which lead to childhood kidney failure. Salll 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 (SalllTBS), we investigated the role of Salll in response to acute kidney injury. Our studies revealed that Salll is expressed in terminally differentiated renal epithelia, including the S3 segment of the proximal tubule, in the mature kidney. SalllTBS 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 SalllTBS mice. Mice containing null alleles of Salll are not protected from acute kidney injury, indicating that expression of a truncated mutant protein from the SalllTBS allele, while causative of congenital anomalies, protects the adult kidney from injury. Our studies further revealed that basal levels of the preconditioning factor heme oxygen-ase-1 are elevated in SalllTBS kidneys, suggesting a mechanism for the relative resistance to injury in this model. Together, these studies establish a functional role for Salll in the response of the adult kidney to acute injury.