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

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

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.

Keywords: DPP-4 inhibition; SDF-1; diabetic nephropathy.

MeSH terms

  • Albuminuria / drug therapy
  • Albuminuria / urine
  • Animals
  • Chemokine CXCL12 / metabolism*
  • Diabetes Mellitus, Type 1 / complications*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / urine
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Glomerular Filtration Rate
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Kidney / blood supply
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology*
  • Linagliptin / therapeutic use*
  • Liraglutide / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Receptors, CXCR4 / antagonists & inhibitors
  • Up-Regulation

Substances

  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Heterocyclic Compounds
  • Hypoglycemic Agents
  • Receptors, CXCR4
  • Linagliptin
  • Liraglutide
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse
  • plerixafor octahydrochloride