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Kidney Int. 2016 Oct;90(4):783-96. doi: 10.1016/j.kint.2016.06.012. Epub 2016 Jul 27.

Stromal cell-derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy.

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Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan. Electronic address:
Division of Metabolism and Clinical Nutrition Science, Akita University Graduate School of Medicine, Akita, Japan.
Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Medicine, University of Toronto, Toronto, Ontario, Canada; The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
Kansai Electric Power Medical Research Institute, Osaka, Japan.


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.


DPP-4 inhibition; SDF-1; diabetic nephropathy

[Indexed for MEDLINE]

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