Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney

Am J Physiol Renal Physiol. 2008 Apr;294(4):F739-47. doi: 10.1152/ajprenal.00508.2007. Epub 2008 Jan 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Urea Nitrogen
  • DNA Primers
  • Gene Expression Regulation
  • Kidney / physiology
  • Kidney / physiopathology
  • Kidney Diseases / complications
  • Kidney Diseases / physiopathology*
  • Kidney Function Tests
  • Mice
  • Mice, Inbred C57BL
  • Nerve Growth Factors / analysis
  • Nerve Growth Factors / genetics*
  • Netrin Receptors
  • Netrin-1
  • Netrins
  • RNA, Messenger / genetics
  • Receptors, Cell Surface / genetics*
  • Renal Circulation* / drug effects
  • Reperfusion Injury / etiology
  • Reperfusion Injury / prevention & control*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Proteins / analysis
  • Tumor Suppressor Proteins / genetics*


  • DNA Primers
  • Nerve Growth Factors
  • Netrin Receptors
  • Netrins
  • Ntn1 protein, mouse
  • Ntn4 protein, mouse
  • RNA, Messenger
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Netrin-1