Journal of Molecular Medicine

, Volume 91, Issue 9, pp 1071–1080

Protective role for netrin-1 during diabetic nephropathy

  • Eunyoung Tak
  • Douglas Ridyard
  • Alexander Badulak
  • Antasia Giebler
  • Uladzimir Shabeka
  • Tilmann Werner
  • Eric Clambey
  • Radu Moldovan
  • Michael A. Zimmerman
  • Holger K. Eltzschig
  • Almut Grenz
Original Article

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

Diabetes Nephropathy Netrin-1 Inflammation Vascular injury Hypoxia 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Eunyoung Tak
    • 1
  • Douglas Ridyard
    • 1
  • Alexander Badulak
    • 1
  • Antasia Giebler
    • 1
  • Uladzimir Shabeka
    • 1
  • Tilmann Werner
    • 2
  • Eric Clambey
    • 1
  • Radu Moldovan
    • 3
  • Michael A. Zimmerman
    • 4
  • Holger K. Eltzschig
    • 1
  • Almut Grenz
    • 1
  1. 1.Department of AnesthesiologyUniversity of Colorado DenverAuroraUSA
  2. 2.Department of AnesthesiologyUniversity Hospital RegensburgRegensburgGermany
  3. 3.Advanced Light Microscopy Core Facility, School of MedicineUniversity of Colorado DenverAuroraUSA
  4. 4.Division of Transplant Surgery, Department of SurgeryUniversity of Colorado DenverAuroraUSA

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