Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney

Yves Gorin, Karen Block, James Hernandez, Basant Bhandari, Brent Wagner, Jeffrey L. Barnes, Hanna E. Abboud

Research output: Contribution to journalArticle

380 Citations (Scopus)

Abstract

Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. We investigated the role of the NAD(P)H oxidase Nox4 in generation of reactive oxygen species (ROS), hypertrophy, and fibronectin expression in a rat model of type 1 diabetes induced by streptozotocin. Phosphorothioated antisense (AS) or sense oligonucleotides for Nox4 were administered for 2 weeks with an osmotic minipump 72 h after streptozotocin treatment. Nox4 protein expression was increased in diabetic kidney cortex compared with non-diabetic controls and was down-regulated in AS-treated animals. AS oligonucleotides inhibited NADPH-dependent ROS generation in renal cortical and glomerular homogenates. ROS generation by intact isolated glomeruli from diabetic animals was increased compared with glomeruli isolated from AS-treated animals. AS treatment reduced whole kidney and glomerular hypertrophy. Moreover, the increased expression of fibronectin protein was markedly reduced in renal cortex including glomeruli of AS-treated diabetic rats. Akt/protein kinase B and ERK1/2, two protein kinases critical for cell growth and hypertrophy, were activated in diabetes, and AS treatment almost abolished their activation. In cultured mesangial cells, high glucose increased NADPH oxidase activity and fibronectin expression, effects that were prevented in cells transfected with AS oligonucleotides. These data establish a role for Nox4 as the major source of ROS in the kidneys during early stages of diabetes and establish that Nox4-derived ROS mediate renal hypertrophy and increased fibronectin expression.

Original languageEnglish (US)
Pages (from-to)39616-39626
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number47
DOIs
StatePublished - Nov 25 2005

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NADPH Oxidase
Fibronectins
Hypertrophy
Reactive Oxygen Species
Kidney
Medical problems
Animals
Antisense Oligonucleotides
Streptozocin
Rats
Proto-Oncogene Proteins c-akt
Cell growth
Kidney Cortex
NADP
Mesangial Cells
Oligonucleotides
Protein Kinases
Diabetic Nephropathies
Type 1 Diabetes Mellitus
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Gorin, Y., Block, K., Hernandez, J., Bhandari, B., Wagner, B., Barnes, J. L., & Abboud, H. E. (2005). Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. Journal of Biological Chemistry, 280(47), 39616-39626. https://doi.org/10.1074/jbc.M502412200

Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. / Gorin, Yves; Block, Karen; Hernandez, James; Bhandari, Basant; Wagner, Brent; Barnes, Jeffrey L.; Abboud, Hanna E.

In: Journal of Biological Chemistry, Vol. 280, No. 47, 25.11.2005, p. 39616-39626.

Research output: Contribution to journalArticle

Gorin, Y, Block, K, Hernandez, J, Bhandari, B, Wagner, B, Barnes, JL & Abboud, HE 2005, 'Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney', Journal of Biological Chemistry, vol. 280, no. 47, pp. 39616-39626. https://doi.org/10.1074/jbc.M502412200
Gorin Y, Block K, Hernandez J, Bhandari B, Wagner B, Barnes JL et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. Journal of Biological Chemistry. 2005 Nov 25;280(47):39616-39626. https://doi.org/10.1074/jbc.M502412200
Gorin, Yves ; Block, Karen ; Hernandez, James ; Bhandari, Basant ; Wagner, Brent ; Barnes, Jeffrey L. ; Abboud, Hanna E. / Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 47. pp. 39616-39626.
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