Netrin-1 overexpression in kidney proximal tubular epithelium ameliorates cisplatin nephrotoxicity

Amala Rajasundari, Laurent Pays, Patrick Mehlen, Ganesan Ramesh

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Netrin-1, a multifunctional laminin-related protein is widely expressed in various tissues, including kidney. The pathophysiological roles of netrin-1 in toxic acute kidney injury are unknown. To determine the role of netrin-1 in cisplatin-induced nephrotoxicity, we used netrin-1 transgenic mice that overexpress netrin-1 in the proximal tubular epithelium using the fatty acid binding protein promoter. Administration of cisplatin caused severe renal injury in WT mice but not in netrin-1 transgenic mice. Functional improvement was associated with better preservation of morphology, reduced cytokine expression and oxidative stress in the kidney, and reduced serum and urine cytokine and chemokine levels of transgenic mice as compared with WT mice. Cisplatin induced an increase in neutrophil infiltration into the kidney of WT mice, which was not significantly reduced in netrin-1 transgenic mice. Interestingly, ischemia reperfusion induced a large increase in apoptosis in WT mice but not in netrin-1 transgenic mice (215±40 vs 94±20 cells/5 HPF (× 400), P<0.0001), which was associated with reduced caspase-3 and p53 activation in the transgenic kidney. These results suggest that netrin-1 protects renal tubular epithelial cells against cisplatin-induced kidney injury by suppressing apoptosis and inflammation.

Original languageEnglish (US)
Pages (from-to)1717-1726
Number of pages10
JournalLaboratory Investigation
Volume91
Issue number12
DOIs
StatePublished - Dec 1 2011

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Cisplatin
Epithelium
Kidney
Transgenic Mice
Apoptosis
Cytokines
netrin-1
Fatty Acid-Binding Proteins
Neutrophil Infiltration
Poisons
Wounds and Injuries
Laminin
Chemokines
Acute Kidney Injury
Caspase 3
Reperfusion
Oxidative Stress
Ischemia
Epithelial Cells
Urine

Keywords

  • GF-b1
  • calcineurin/NFAT
  • iabetic nephropathy
  • orcantharidin
  • ubulointerstitial fibrosis
  • xtracellular matrix

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

Netrin-1 overexpression in kidney proximal tubular epithelium ameliorates cisplatin nephrotoxicity. / Rajasundari, Amala; Pays, Laurent; Mehlen, Patrick; Ramesh, Ganesan.

In: Laboratory Investigation, Vol. 91, No. 12, 01.12.2011, p. 1717-1726.

Research output: Contribution to journalArticle

Rajasundari, Amala ; Pays, Laurent ; Mehlen, Patrick ; Ramesh, Ganesan. / Netrin-1 overexpression in kidney proximal tubular epithelium ameliorates cisplatin nephrotoxicity. In: Laboratory Investigation. 2011 ; Vol. 91, No. 12. pp. 1717-1726.
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