Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney.
Endogenous mechanisms exist to limit inflammation. One such molecule is netrin. This study examined the impact of ischemia-reperfusion (I/R) on netrin expression and the role of netrin in preventing renal inflammation and injury. All three isoforms of netrin (1, 3, and 4) are expressed in normal kidney. I/R significantly downregulated netrin-1 and -4 mRNA expression, whereas expression of netrin-3 was moderately upregulated at 24 h of reperfusion. The netrin receptor UNC5B mRNA increased at 3 h and but decreased at later time points. Expression of a second netrin receptor, DCC, was not altered significantly. I/R was associated with dramatic changes in netrin-1 protein abundance and localization. Netrin-1 protein levels increased between 3 and 24 h after reperfusion. Immunolocalization showed an interstitial distribution of netrin-1 in sham-operated kidneys which colocalized with Von Willebrand Factor suggesting the presence of netrin-1 in peritubular capillaries. After I/R, interstitial netrin-1 expression decreased and netrin-1 appeared in tubular epithelial cells. By 72 h after reperfusion, netrin-1 reappeared in the interstitium while tubular epithelial staining decreased significantly. Downregulation of netrin-1 in the interstitium corresponded with increased MCP-1 and IL-6 expression and infiltration of leukocytes into the reperfused kidney. Administration of recombinant netrin-1 significantly improved kidney function (blood urea nitrogen: 161 +/- 7 vs. 104 +/- 24 mg/dl, creatinine: 1.3 +/- 0.07 vs. 0.75 +/- 0.16 mg/dl, P < 0.05 at 24 h) and reduced tubular damage and leukocyte infiltration in the outer medulla. These results suggest that downregulation of netrin-1 in vascular endothelial cells may promote endothelial cell activation and infiltration of leukocytes into the kidney thereby enhancing tubular injury.
Wang
Weiwei
W
Division of Nephrology, H040, Pennsylvania State Univ. College of Medicine, 500 Univ. Drive, Hershey, PA 17033, USA.
Reeves
W Brian
WB
Ramesh
Ganesan
G
D000818:Animals; D001806:Blood Urea Nitrogen; D017931:DNA Primers; D005786:Gene Expression Regulation; D007668:Kidney / Q000502:physiology / Q000503:physiopathology; D007674:Kidney Diseases / Q000150:complications / Q000503:physiopathology*; D007677:Kidney Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000032:analysis / Q000235:genetics*; D000075386:Netrin Receptors; D000075388:Netrin-1; D000075385:Netrins; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics*
D017931:DNA Primers; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D000075385:Netrins; C000617353:Ntn1 protein, mouse; C416214:Ntn4 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1