title: Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis.
abstract: Renal fibrosis is the common pathway of progression for patients with CKD and chronic renal allograft injury (CAI), but the underlying mechanisms remain obscure. We performed a meta-analysis in human kidney biopsy specimens with CAI, incorporating data available publicly and from our Genomics of Chronic Renal Allograft Rejection study. We identified anSrcfamily tyrosine kinase, hematopoietic cell kinase (Hck), as upregulated in allografts in CAI. Querying the Kinase Inhibitor Resource database revealed that dasatinib, a Food and Drug Administration-approved drug, potently bindsHckwith high selectivity.In vitro,Hckoverexpression activated theTGF-β/Smad3pathway, whereasHCKknockdown inhibited it. Treatment of tubular cells with dasatinib reduced the expression ofCol1a1Dasatinib also reduced proliferation andα-SMAexpression in fibroblasts. In a murine model with unilateral ureteric obstruction, pretreatment with dasatinib significantly reduced the upregulation of profibrotic markers, phosphorylation of Smad3, and renal fibrosis observed in kidneys pretreated with vehicle alone. Dasatinib treatment also improved renal function, reduced albuminuria, and inhibited expression of profibrotic markers in animal models with lupus nephritis and folic acid nephropathy. These data suggest thatHckis a key mediator of renal fibrosis and dasatinib could be developed as an antifibrotic drug.
authors.affiliation: Divisions of *Nephrology and.
authors.forename: Chengguo
authors.initials: C
authors.lastname: Wei
authors.affiliation: Departments of Genetics and Genomic Sciences and.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Divisions of *Nephrology and.
authors.forename: Madhav C
authors.initials: MC
authors.lastname: Menon
authors.affiliation: Divisions of *Nephrology and.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Divisions of *Nephrology and.
authors.forename: Jia
authors.initials: J
authors.lastname: Fu
authors.affiliation: Departments of Genetics and Genomic Sciences and.
authors.forename: Brian
authors.initials: B
authors.lastname: Kidd
authors.affiliation: Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia; and.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Keung
authors.affiliation: Divisions of *Nephrology and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Woytovich
authors.affiliation: Divisions of *Nephrology and.
authors.forename: Ilana
authors.initials: I
authors.lastname: Greene
authors.affiliation: Divisions of *Nephrology and.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Renal Pathology, and.
authors.forename: Fadi
authors.initials: F
authors.lastname: Salem
authors.affiliation: Divisions of *Nephrology and.
authors.forename: Zhengzi
authors.initials: Z
authors.lastname: Yi
authors.affiliation: Divisions of *Nephrology and cijiang.he@mssm.edu joel.dudley@mssm.edu barbara.murphy@mssm.edu.|Renal Section, Department of Medicine, James J. Peter Veterans Affairs Medical Center, New York, New York.
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.affiliation: Departments of Genetics and Genomic Sciences and cijiang.he@mssm.edu joel.dudley@mssm.edu barbara.murphy@mssm.edu.|Health Policy and Research, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.affiliation: Divisions of *Nephrology and cijiang.he@mssm.edu joel.dudley@mssm.edu barbara.murphy@mssm.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Murphy
mesh_terms: D000818:Animals; D005260:Female; D005355:Fibrosis / Q000235:genetics; D023281:Genomics; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics*; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications / Q000235:genetics*; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics* / Q000502:physiology*
chemical_list: C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck
keywords: Hck; chronic renal allograft injury; dasatinib; renal fibrosis