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Silencing of tissue factor by antisense deoxyoligonucleotide prevents monocrotaline/LPS renal injury in mice

  • Organ Toxicity and Mechanisms
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Abstract

Tissue factor (TF) is involved in monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity. It is not known whether MCT/LPS can cause renal toxicity and whether TF is involved in this toxicity. Thus, the present study was undertaken to investigate the potential renal toxicity after MCT/LPS co-treatment and the involvement of TF in this toxicity. MCT was delivered to ND4 male mice (200 mg/kg) per os followed 4 h later by treatment with LPS ip (6 mg/kg) to investigate its effect on kidney. We injected TF antisense oligonucleotide (TF-AS) intravenously (i.v) in mice prior to LPS treatment, to block TF, and measured their blood urea nitrogen (BUN), creatinine (CRE), alkaline phosphatase (ALP), and potassium. In MCT/LPS co-treated group, fibrin was detected on the glomerular capillary lumina, distal tubules of renal cortex, and the necrotic tubules of renal medulla. An elevation of BUN, creatinine, and the BUN/creatinine ratio was seen in mice with MCT/LPS co-treatment, compared to animals receiving LPS or MCT alone. Simultaneously, an aggressive tubular necrosis was seen in the medullary tubules in the same group which may account for the oliguria observed in these animals. Fourfold inductions in the plasma TF level was detected at 10 h after MCT/LPS co-treatment which increased to 18-fold at 24 h. Increased blood level of leptin, interleukin-6 (IL-6) and downregulation of tubular chemokine (C-X-C motif) ligand 16 (CXCL16) are characteristic features in MCT/LPS co-treated animal. On the other hand, mice injected with TF-AS in the presence of MCT/LPS co-treatment showed no elevation of the blood BUN, creatinine, potassium, and normal levels of the proinflammatory molecules. TF-AS injection significantly prevented glomerular and tubular fibrin deposition, tubular necrosis, and improvement of the animal survivability. Renal toxicity involving TF can be prevented successfully by the use of TF-AS.

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Acknowledgments

The authors wish to thank Mr. Rajnish Sahu (NCNPR, University of Mississippi) for his help in the use of fluorescent microscope. This work was supported in part by the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative agreement [58-6408-2-0009] and US Food and Drug Administration [5U01FD002071-09 and 1U01FD003871-011].

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Authors and Affiliations

  1. National Center For Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, 38677, USA

    Mohamed Sadek Abdel-Bakky, Mohamed A. Hammad, Larry A. Walker & Mohammad K. Ashfaq

  2. Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS, 38677, USA

    Mohamed A. Hammad & Larry A. Walker

  3. Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

    Mohamed Sadek Abdel-Bakky

  4. Center for Engineering in Medicine and Surgical Services, Harvard Medical School, Massachusetts General Hospital, Boston, MA, 02114, USA

    Mohamed A. Hammad

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  1. Mohamed Sadek Abdel-Bakky
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  2. Mohamed A. Hammad
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Correspondence to Mohammad K. Ashfaq.

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Mohamed Sadek Abdel-Bakky and Mohamed A. Hammad have equally contributed to this work.

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Abdel-Bakky, M.S., Hammad, M.A., Walker, L.A. et al. Silencing of tissue factor by antisense deoxyoligonucleotide prevents monocrotaline/LPS renal injury in mice. Arch Toxicol 85, 1245–1256 (2011). https://doi.org/10.1007/s00204-011-0663-8

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