title: 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.
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.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hari
authors.initials: H
authors.lastname: Hendarto
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Inoguchi
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Noriko
authors.initials: N
authors.lastname: Ikeda
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takei
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yokomizo
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hirata
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sonoda
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000419:Albuminuria / Q000517:prevention & control*; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology*; D000069450:Liraglutide; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D009097:Multienzyme Complexes; D013449:Sulfonamides; C017759:9-(tetrahydro-2-furyl)-adenine; D013311:Streptozocin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D017868:Cyclic AMP-Dependent Protein Kinases; D000225:Adenine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide