title: Hypertensive renal injury is associated with gene variation affecting immune signaling.
abstract: BACKGROUND
  The spontaneously hypertensive rat (SHR) strain exists in lines that contrast strongly in susceptibility to renal injury in hypertension. These inbred lines share common ancestry, and only 13% of their genomes arise from different ancestors.
  
  
  RESULTS
  We used next gen sequencing to detect natural allelic variation in 5 genes of the immunoreceptor signaling pathway (IgH, Dok3, Src, Syk, and JunD) that arise from different ancestors in the injury-prone SHR-A3 and the resistant SHR-B2 lines. We created an intercross between these lines, and in the F2 progeny, we observed that the inheritance of haplotype blocks containing the SHR-A3 alleles of these 5 genes correlated with increased albuminuria and histological measures of renal injury. To test whether accumulated genetic variation in this pathway may create a therapeutic target in hypertensive renal injury, rats of both lines were treated with the immunosuppressant mycophenolate mofetil (MMF). MMF reduced proteinuria (albumin to creatinine ratio) from 6.6 to 1.2 mg/mg (P<0.001) in SHR-A3. Glomerular injury scores were reduced in MMF-treated SHR-A3 from 1.6 to 1.4 (P<0.002). Tubulo-interstitial injury was reduced in MMF-treated SHR-A3 from 2.62 to 2.0 (P=0.001). MMF treatment also reduced renal fibrosis in SHR-A3 (3.9 versus 2.0; P<0.001).
  
  
  CONCLUSIONS
  Polygenic susceptibility to renal injury in hypertension arises in association with genetic variation in genes that participate in immune responses and is dramatically improved by reduction of immune system activity.
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Braun
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Herring
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
authors.forename: Nisha
authors.initials: N
authors.lastname: Gokul
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
authors.forename: Monique
authors.initials: M
authors.lastname: Monita
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bell
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
authors.forename: Manuel L
authors.initials: ML
authors.lastname: Gonzalez-Garay
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Wenderfer
authors.affiliation: From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston. peter.a.doris@uth.tmc.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Doris
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology; D000483:Alleles; D000818:Animals; D001794:Blood Pressure; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005919:Glomerular Filtration Rate; D006239:Haplotypes; D006973:Hypertension / Q000150:complications; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
chemical_list: D007166:Immunosuppressive Agents; D011971:Receptors, Immunologic; D009173:Mycophenolic Acid
keywords: genome; hypertension; kidney; renal disease