title: Role of TGF-alpha in the progression of diabetic kidney disease.
abstract: Transforming growth factor-alpha (TGFA) has been shown to play a role in experimental chronic kidney disease associated with nephron reduction, while its role in diabetic kidney disease (DKD) is unknown. We show here that intrarenalTGFAmRNA expression, as well as urine and serum TGFA, are increased in human DKD. We used a TGFA neutralizing antibody to determine the role of TGFA in two models of renal disease, the remnant surgical reduction model and the uninephrectomized (uniNx)db/dbDKD model. In addition, the contribution of TGFA to DKD progression was examined using an adeno-associated virus approach to increase circulating TGFA in experimental DKD. In vivo blockade of TGFA attenuated kidney disease progression in both nondiabetic129S6nephron reduction and Type 2 diabetic uniNxdb/dbmodels, whereas overexpression of TGFA in uniNxdb/dbmodel accelerated renal disease. Therapeutic activity of the TGFA antibody was enhanced with renin angiotensin system inhibition with further improvement in renal parameters. These findings suggest a pathologic contribution of TGFA in DKD and support the possibility that therapeutic administration of neutralizing antibodies could provide a novel treatment for the disease.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana heuer_josef_g@lilly.com.
authors.forename: Josef G
authors.initials: JG
authors.lastname: Heuer
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Harlan
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Yang
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Dianna L
authors.initials: DL
authors.lastname: Jaqua
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Boyles
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Heinz-Taheny
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: John M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Tao
authors.initials: T
authors.lastname: Wei
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Hui-Rong
authors.initials: HR
authors.lastname: Qian
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Derrick R
authors.initials: DR
authors.lastname: Witcher
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001794:Blood Pressure; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005919:Glomerular Filtration Rate; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008875:Middle Aged; D009392:Nephrectomy; D010766:Phosphorylation; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D016211:Transforming Growth Factor alpha; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: TGFa; diabetic kidney disease