title: Stromal cell-derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy.
abstract: The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic-resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic-prone mice, but not in kidneys from diabetic-resistant mice. The DPP-4 inhibitor linagliptin, but not the GLP-1R agonist liraglutide, further augmented renal SDF-1 expression in both Glp1r(+/+) and Glp1r(-/-) diabetic-prone mice. Along with upregulation of renal SDF-1 expression, the progression of albuminuria, glomerulosclerosis, periglomerular fibrosis, podocyte loss, and renal oxidative stress was suppressed in linagliptin-treated Glp1r(+/+) diabetic-prone mice. Linagliptin treatment increased urinary sodium excretion and attenuated the increase in glomerular filtration rate which reflects glomerular hypertension and hyperfiltration. In contrast, selective SDF-1 receptor blockade with AMD3100 reduced urinary sodium excretion and aggravated glomerular hypertension in the Glp1r(+/+) diabetic-prone mice. Thus, DPP-4 inhibition, independent of GLP-1R signaling, contributes to protection of the diabetic kidney through SDF-1-dependent antioxidative and antifibrotic effects and amelioration of adverse renal hemodynamics.
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takashima
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan. Electronic address: hirofuji@gipc.akita-u.ac.jp.
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: 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: 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: 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: Tsukasa
authors.initials: T
authors.lastname: Morii
authors.affiliation: Division of Metabolism and Clinical Nutrition Science, 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: Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 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 Medical Research Institute, 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: D000419:Albuminuria / Q000188:drug therapy / Q000652:urine; D000818:Animals; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000652:urine; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005919:Glomerular Filtration Rate; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000069476:Linagliptin / Q000627:therapeutic use*; D000069450:Liraglutide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D015854:Up-Regulation; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D006571:Heterocyclic Compounds; D007004:Hypoglycemic Agents; D019718:Receptors, CXCR4; D000069476:Linagliptin; D000069450:Liraglutide; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; C088327:plerixafor; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: DPP-4 inhibition; SDF-1; diabetic nephropathy