Partial netrin-1 deficiency aggravates acute kidney injury

Almut Grenz, Julee H. Dalton, Jessica D. Bauerle, Alexander Badulak, Douglas Ridyard, Aneta Gandjeva, Carol M. Aherne, Kelley S. Brodsky, Jae Hwan Kim, Rubin M. Tuder, Holger K. Eltzschig

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Abstract

The netrin family of secreted proteins provides migrational cues in the developing central nervous system. Recently, netrins have also been shown to regulate diverse processes beyond their functions in the brain, incluing the ochrestration of inflammatory events. Particularly netrin-1 has been implicated in dampening hypoxia-induced inflammation. Here, we hypothesized an anti-inflammatory role of endogenous netrin-1 in acute kidney injury (AKI). As homozygous deletion of netrin-1 is lethal, we studied mice with partial netrin-1 deletion (Ntn-1+/- mice) as a genetic model. In fact, Ntn-1+/- mice showed attenuated Ntn-1 levels at baseline and following ischemic AKI. Functional studies of AKI induced by 30 min of renal ischemia and reperfusion revealed enhanced kidney dysfunction in Ntn-1+/- mice as assessed by measurements of glomerular filtration, urine flow rate, urine electrolytes, serum creatinine and creatinine clearance. Consistent with these findings, histological studies indicated a more severe degree kidney injury. Similarly, elevations of renal and systemic inflammatory markers were enhanced in mice with partial netrin-1 deficiency. Finally, treatment of Ntn-1+/- mice with exogenous netrin-1 restored a normal phenotype during AKI. Taking together, these studies implicate endogenous netrin-1 in attenuating renal inflammation during AKI.

Original languageEnglish
Article numbere14812
JournalPLoS One
Volume6
Issue number5
DOIs
Publication statusPublished - 2011 May 25

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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Grenz, A., Dalton, J. H., Bauerle, J. D., Badulak, A., Ridyard, D., Gandjeva, A., Aherne, C. M., Brodsky, K. S., Kim, J. H., Tuder, R. M., & Eltzschig, H. K. (2011). Partial netrin-1 deficiency aggravates acute kidney injury. PLoS One, 6(5), [e14812]. https://doi.org/10.1371/journal.pone.0014812