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Protective role for netrin-1 during diabetic nephropathy. J Mol Med (Berl) 2013 Sep;91(9):1071-80

Date

05/03/2013

Pubmed ID

23636509

Pubmed Central ID

PMC3766438

DOI

10.1007/s00109-013-1041-1

Scopus ID

2-s2.0-84884256510   19 Citations

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.

Author List

Tak E, Ridyard D, Badulak A, Giebler A, Shabeka U, Werner T, Clambey E, Moldovan R, Zimmerman MA, Eltzschig HK, Grenz A

Author

Michael A. Zimmerman MD, FACS Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Albuminuria
Animals
Diabetes Mellitus, Experimental
Diabetic Nephropathies
Kidney
Mice
Mice, Transgenic
Nerve Growth Factors
Netrin-1
Receptor, Adenosine A2B
Recombinant Proteins
Tumor Suppressor Proteins
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0