title: The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential.
abstract: Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Morii
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujishima
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Hosoba
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tsukiyama
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Narita
authors.affiliation: Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Takamune
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: 1] Department of Medicine, University of Toronto, Toronto, Ontario, Canada [2] The Lunenfeld-Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.affiliation: Kansai Electric Power Hospital, Osaka, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000032:analysis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D000069450:Liraglutide; D008297:Male; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000032:analysis; D018384:Oxidative Stress; D018027:Receptors, Glucagon / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D009569:Nitric Oxide; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D019255:NADPH Oxidases; D017868:Cyclic AMP-Dependent Protein Kinases