Role of TGF-alpha in the progression of diabetic kidney disease

被引：25

作者：

Heuer, Josef G. ^{[1
]}

Harlan, Shannon M. ^{[1
]}

Yang, Derek D. ^{[1
]}

Jaqua, Dianna L. ^{[1
]}

Boyles, Jeffrey S. ^{[1
]}

Wilson, Jonathan M. ^{[1
]}

Heinz-Taheny, Kathleen M. ^{[1
]}

Sullivan, John M. ^{[1
]}

Wei, Tao ^{[1
]}

Qian, Hui-Rong ^{[1
]}

Witcher, Derrick R. ^{[1
]}

Breyer, Matthew D. ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY | 2017年 / 312卷 / 06期

关键词：

diabetic kidney disease; TGFa; EPIDERMAL-GROWTH-FACTOR; FACTOR RECEPTOR INHIBITION; EGF RECEPTOR; ANGIOTENSIN-II; RENAL-DISEASE; NEPHROPATHY; LIGANDS; EXPRESSION; INJURY; ACTIVATION;

D O I：

10.1152/ajprenal.00443.2016

中图分类号：

Q4 [生理学];

学科分类号：

071003 ;

摘要：

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 intrarenal TGFA mRNA 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 unine-phrectomized (uniNx) db/db DKD 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 nondiabetic 129S6 nephron reduction and Type 2 diabetic uniNx db/db models, whereas overexpression of TGFA in uniNx db/db model 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.

引用

页码：F951 / F962

页数：12

共 53 条

[1] Generation and Activity of a Humanized Monoclonal Antibody That Selectively Neutralizes the Epidermal Growth Factor Receptor Ligands Transforming Growth Factor-α and Epiregulin [J].

Beidler, Catherine B. ;

Petrovan, Ramona J. ;

Conner, Elaine M. ;

Boyles, Jeffrey S. ;

Yang, Derek D. ;

Harlan, Shannon M. ;

Chu, Shaoyou ;

Ellis, Bernice ;

Datta-Mannan, Amita ;

Johnson, Robert L. ;

Stauber, Anja ;

Witcher, Derrick R. ;

Breyer, Matthew D. ;

Heuer, Josef G. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2014, 349 (02) :330-343

[2] Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis [J].

Bollee, Guillaume ;

Flamant, Martin ;

Schordan, Sandra ;

Fligny, Cecile ;

Rumpel, Elisabeth ;

Milon, Marine ;

Schordan, Eric ;

Sabaa, Nathalie ;

Vandermeersch, Sophie ;

Galaup, Ariane ;

Rodenas, Anita ;

Casal, Ibrahim ;

Sunnarborg, Susan W. ;

Salant, David J. ;

Kopp, Jeffrey B. ;

Threadgill, David W. ;

Quaggin, Susan E. ;

Dussaule, Jean-Claude ;

Germain, Stephane ;

Mesnard, Laurent ;

Endlich, Karlhans ;

Boucheix, Claude ;

Belenfant, Xavier ;

Callard, Patrice ;

Endlich, Nicole ;

Tharaux, Pierre-Louis .

NATURE MEDICINE, 2011, 17 (10) :1242-U272

[3] Structural basis of selectivity and neutralizing activity of a TGFα/epiregulin specific antibody [J].

Boyles, Jeffrey S. ;

Atwell, Shane ;

Druzina, Zhanna ;

Heuer, Josef G. ;

Witcher, Derrick R. .

PROTEIN SCIENCE, 2016, 25 (11) :2028-2036

[4]

Breyer MD, 2011, CONTRIB NEPHROL, V170, P156, DOI 10.1159/000325651

[5] THE BIOCHEMISTRY AND PHYSIOLOGY OF THE RECEPTOR-KINASE FOR EPIDERMAL GROWTH-FACTOR [J].

CARPENTER, G .

MOLECULAR AND CELLULAR ENDOCRINOLOGY, 1983, 31 (01) :1-19

[6] EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy [J].

Chen, Jianchun ;

Chen, Jian-Kang ;

Harris, Raymond C. .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2015, 26 (05) :1115-1125

[7] Angiotensin II Induces Epithelial-to-Mesenchymal Transition in Renal Epithelial Cells through Reactive Oxygen Species/Src/Caveolin-Mediated Activation of an Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase Signaling Pathway [J].

Chen, Jianchun ;

Chen, Jian-Kang ;

Harris, Raymond C. .

MOLECULAR AND CELLULAR BIOLOGY, 2012, 32 (05) :981-991

[8] EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis [J].

Chen, Jianchun ;

Chen, Jian-Kang ;

Nagai, Kojiro ;

Plieth, David ;

Tan, Mingqi ;

Lee, Tang-Cheng ;

Threadgill, David W. ;

Neilson, Eric G. ;

Harris, Raymond C. .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2012, 23 (02) :215-224

[9] Physician conformity and patient adherence to ACE inhibitors and ARBs in patients with diabetes, with and without renal disease and hypertension, in a medicaid managed care organization [J].

Cooke, Catherine E. ;

Fatodu, Hugh .

JOURNAL OF MANAGED CARE PHARMACY, 2006, 12 (08) :649-655

[10] Impact of Age at Administration, Lysosomal Storage, and Transgene Regulatory Elements on AAV2/8-Mediated Rat Liver Transduction [J].

Cotugno, Gabriella ;

Annunziata, Patrizia ;

Barone, Maria Vittoria ;

Karali, Marianthi ;

Banfi, Sandro ;

Auricchio, Alberto .

PLOS ONE, 2012, 7 (03)

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