TY - JOUR
T1 - Partial netrin-1 deficiency aggravates acute kidney injury
AU - Grenz, Almut
AU - Dalton, Julee H.
AU - Bauerle, Jessica D.
AU - Badulak, Alexander
AU - Ridyard, Douglas
AU - Gandjeva, Aneta
AU - Aherne, Carol M.
AU - Brodsky, Kelley S.
AU - Kim, Jae Hwan
AU - Tuder, Rubin M.
AU - Eltzschig, Holger K.
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79956276662&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0014812
DO - 10.1371/journal.pone.0014812
M3 - Article
C2 - 21625583
AN - SCOPUS:79956276662
SN - 1932-6203
VL - 6
JO - PloS one
JF - PloS one
IS - 5
M1 - e14812
ER -