title: Transcription factor avian erythroblastosis virus E26 oncogen homolog-1 is a novel mediator of renal injury in salt-sensitive hypertension.
abstract: Transcription factor E26 transformation-specific sequence-1 (ETS-1) is a transcription factor that regulates the expression of a variety of genes, including growth factors, chemokines, and adhesion molecules. We recently demonstrated that angiotensin II increases the glomerular expression of ETS-1 and that blockade of ETS-1 ameliorates the profibrotic and proinflammatory effects of angiotensin II. The Dahl salt-sensitive rat is a paradigm of salt-sensitive hypertension associated with local activation of the renin-angiotensin system. In these studies, we determined whether: (1) salt-sensitive hypertension is associated with renal expression of ETS-1 and (2) ETS-1 participates in the development of end-organ injury in salt-sensitive hypertension. Dahl salt-sensitive rats were fed a normal-salt diet (0.5% NaCl diet) or a high-salt diet (4% NaCl) for 4 weeks. Separate groups on high-salt diet received an ETS-1 dominant-negative peptide (10 mg/kg/d), an inactive ETS-1 mutant peptide (10 mg/kg/d), the angiotensin II type 1 receptor blocker candesartan (10 mg/kg/d), or the combination high-salt diet/dominant-negative peptide/angiotensin II type 1 receptor blocker for 4 weeks. High-salt diet rats had a significant increase in the glomerular expression of the phosphorylated ETS-1 that was prevented by angiotensin II type 1 receptor blocker. ETS-1 blockade reduced proteinuria, glomerular injury score, fibronectin expression, urinary transforming growth factor-β excretion, and macrophage infiltration. Angiotensin II type 1 receptor blocker reduced proteinuria, glomerular injury score, and macrophage infiltration, whereas concomitant ETS-1 blockade and angiotensin II type 1 receptor blocker had additive effects and reduced interstitial fibrosis. Our studies demonstrated that salt-sensitive hypertension results in increased glomerular expression of phosphorylated ETS-1 and suggested that ETS-1 plays an important role in the pathogenesis of end-organ injury in salt-sensitive hypertension.
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Wenguang
authors.initials: W
authors.lastname: Feng
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Phillip
authors.initials: P
authors.lastname: Chumley
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Minolfa C
authors.initials: MC
authors.lastname: Prieto
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Kayoko
authors.initials: K
authors.lastname: Miyada
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Dale M
authors.initials: DM
authors.lastname: Seth
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Huma
authors.initials: H
authors.lastname: Fatima
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Ping
authors.initials: P
authors.lastname: Hua
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rezonzew
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sanders
authors.affiliation: From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.). jaimese@mskcc.org.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Jaimes
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D050784:Proto-Oncogene Protein c-ets-1 / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D020303:Rats, Inbred Dahl
chemical_list: D000809:Angiotensins; C494043:Ets1 protein, rat; D050784:Proto-Oncogene Protein c-ets-1; D004247:DNA
keywords: Dahl salt-sensitive rats; angiotensins; hypertension; kidney