GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases

Hari Hendarto, Toyoshi Inoguchi, Yasutaka Maeda, Noriko Ikeda, Jing Zheng, Ryoko Takei, Hisashi Yokomizo, Eiichi Hirata, Noriyuki Sonoda, Ryoichi Takayanagi

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Abstract

Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular and renal diseases but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits oxidative stress and albuminuria in streptozotocin (STZ)-induced type 1 diabetes mellitus rats, via a protein kinase A (PKA)-mediated inhibition of renal NAD(P)H oxidases. Diabetic rats were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Oxidative stress markers (urinary 8-hydroxy-2′-deoxyguanosine and renal dihydroethidium staining), expression of renal NAD(P)H oxidase components, transforming growth factor-β (TGF-β), fibronectin and urinary albumin excretion were measured. In vitro effect of liraglutide was evaluated using cultured renal mesangial cells. Administration of liraglutide did not affect plasma glucose levels or body weights in STZ diabetic rats, but normalized oxidative stress markers, expression of NAD(P)H oxidase components, TGF-β, fibronectin in renal tissues and urinary albumin excretion, all of which were significantly increased in diabetic rats. In addition, in cultured renal mesangial cells, incubation with liraglutide for 48 h inhibited NAD(P)H-dependent superoxide production evaluated by lucigenin chemiluminescence in a dose-dependent manner. This effect was reversed by both PKA inhibitor H89 and adenylate cyclase inhibitor SQ22536, but not by Epac2 inhibition via its small interfering RNA. Liraglutide may have a direct beneficial effect on oxidative stress and diabetic nephropathy via a PKA-mediated inhibition of renal NAD(P)H oxidase, independently of a glucose-lowering effect.

Original languageEnglish
Pages (from-to)1422-1434
Number of pages13
JournalMetabolism: Clinical and Experimental
Volume61
Issue number10
DOIs
Publication statusPublished - Oct 1 2012

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Glucagon-Like Peptide 1
Albuminuria
Streptozocin
Cyclic AMP-Dependent Protein Kinases
Oxidative Stress
Mesangial Cells
Transforming Growth Factors
Kidney
Fibronectins
Albumins
Glucose
NADPH Oxidase
Diabetic Nephropathies
Subcutaneous Injections
Protein Kinase Inhibitors
Luminescence
Type 1 Diabetes Mellitus
Superoxides
NAD
Small Interfering RNA

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. / Hendarto, Hari; Inoguchi, Toyoshi; Maeda, Yasutaka; Ikeda, Noriko; Zheng, Jing; Takei, Ryoko; Yokomizo, Hisashi; Hirata, Eiichi; Sonoda, Noriyuki; Takayanagi, Ryoichi.

In: Metabolism: Clinical and Experimental, Vol. 61, No. 10, 01.10.2012, p. 1422-1434.

Research output: Contribution to journalArticle

Hendarto, Hari ; Inoguchi, Toyoshi ; Maeda, Yasutaka ; Ikeda, Noriko ; Zheng, Jing ; Takei, Ryoko ; Yokomizo, Hisashi ; Hirata, Eiichi ; Sonoda, Noriyuki ; Takayanagi, Ryoichi. / GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. In: Metabolism: Clinical and Experimental. 2012 ; Vol. 61, No. 10. pp. 1422-1434.
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AU - Inoguchi, Toyoshi

AU - Maeda, Yasutaka

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AU - Zheng, Jing

AU - Takei, Ryoko

AU - Yokomizo, Hisashi

AU - Hirata, Eiichi

AU - Sonoda, Noriyuki

AU - Takayanagi, Ryoichi

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