Journal of Molecular Medicine

, Volume 91, Issue 9, pp 1071–1080

Protective role for netrin-1 during diabetic nephropathy

Authors

  • Eunyoung Tak
    • Department of AnesthesiologyUniversity of Colorado Denver
  • Douglas Ridyard
    • Department of AnesthesiologyUniversity of Colorado Denver
  • Alexander Badulak
    • Department of AnesthesiologyUniversity of Colorado Denver
  • Antasia Giebler
    • Department of AnesthesiologyUniversity of Colorado Denver
  • Uladzimir Shabeka
    • Department of AnesthesiologyUniversity of Colorado Denver
  • Tilmann Werner
    • Department of AnesthesiologyUniversity Hospital Regensburg
  • Eric Clambey
    • Department of AnesthesiologyUniversity of Colorado Denver
  • Radu Moldovan
    • Advanced Light Microscopy Core Facility, School of MedicineUniversity of Colorado Denver
  • Michael A. Zimmerman
    • Division of Transplant Surgery, Department of SurgeryUniversity of Colorado Denver
  • Holger K. Eltzschig
    • Department of AnesthesiologyUniversity of Colorado Denver
    • Department of AnesthesiologyUniversity of Colorado Denver
Original Article

DOI: 10.1007/s00109-013-1041-1

Cite this article as:
Tak, E., Ridyard, D., Badulak, A. et al. J Mol Med (2013) 91: 1071. doi:10.1007/s00109-013-1041-1

Abstract

Recent studies implicate neuronal guidance molecules in the orchestration of inflammatory events. For example, previous studies demonstrate a functional role for netrin-1 in attenuating acute kidney injury. Here, we hypothesized a kidney-protective role for netrin-1 during chronic kidney disease, such as occurs during diabetic nephropathy. To study the role of netrin-1 during diabetic nephropathy, we induced diabetes in mice at the age of 8 weeks by streptocotozin (STZ) treatment. Sixteen weeks after STZ treatment, we examined the kidneys. Initial studies in wild-type mice demonstrated robust induction of renal, urinary, and plasma netrin-1 protein levels during diabetic nephropathy. Subsequent genetic studies in mice with partial netrin-1 deficiency (Ntrn1+/ mice) revealed a more severe degree of diabetic nephropathy, including more severe loss of kidney function (albuminuria, glomerular filtration rate, histology). We subsequently performed pharmacologic studies with recombinant netrin-1 treatment given continuously via osmotic pump. Indeed, netrin-1 treatment was associated with attenuated albuminuria and improved histologic scores for diabetic nephropathy compared to controls. Consistent with previous studies implicating purinergic signaling in netrin-1-elicited tissue protection, mice deficient in the Adora2b adenosine receptor were not protected. Taken together, these studies demonstrate a functional role for endogenous netrin-1 in attenuating diabetic kidney disease.

Keywords

DiabetesNephropathyNetrin-1InflammationVascular injuryHypoxia

Copyright information

© Springer-Verlag Berlin Heidelberg 2013