title: Netrin-1 overexpression in kidney proximal tubular epithelium ameliorates cisplatin nephrotoxicity.
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.
authors.affiliation: Department of Medicine and Vascular Biology Center, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Amala
authors.initials: A
authors.lastname: Rajasundari
authors.forename: Laurent
authors.initials: L
authors.lastname: Pays
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects*; D016207:Cytokines / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D020556:Neutrophil Infiltration; D018384:Oxidative Stress; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D016207:Cytokines; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D002945:Cisplatin