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

Weiwei Wang, W. Brian Reeves, Ganesan Ramesh

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F739-F747
JournalAmerican Journal of Physiology - Renal Physiology
Volume294
Issue number4
DOIs
StatePublished - Apr 1 2008

Fingerprint

Reperfusion Injury
Kidney
Wounds and Injuries
Reperfusion
Ischemia
Leukocytes
Down-Regulation
netrin-1
Endothelial Cells
Inflammation
Messenger RNA
Blood Urea Nitrogen
von Willebrand Factor
Interleukin-6
Creatinine
Protein Isoforms
Proteins
Epithelial Cells
Staining and Labeling

Keywords

  • Chemokine
  • Endothelial cell
  • Inflammation
  • Netrin-4

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney. / Wang, Weiwei; Reeves, W. Brian; Ramesh, Ganesan.

In: American Journal of Physiology - Renal Physiology, Vol. 294, No. 4, 01.04.2008, p. F739-F747.

Research output: Contribution to journalArticle

Wang, Weiwei ; Reeves, W. Brian ; Ramesh, Ganesan. / Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney. In: American Journal of Physiology - Renal Physiology. 2008 ; Vol. 294, No. 4. pp. F739-F747.
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