Nitroglycerin, a nitric oxide generator attenuates ferric nitrilotriacetate-induced renal oxidative stress, hyperproliferative response and necrosis in ddY mice.

Abstract

Nitric oxide (NO) is a short lived, readily diffusible intracellular messenger molecule associated with multiple organ-specific regulatory functions. In this communication, we elucidate the effect of exogenous NO administration, using nitroglycerin (GTN), on ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative stress, hyperproliferative response and necrosis in ddY mice. Fe-NTA is a known complete renal carcinogen as well as renal and hepatic tumor promoter, which act by generating oxidative stress in the tissues. GTN treatment to ddY mice prior to Fe-NTA administration resulted in a highly significant protection against Fe-NTA-induced renal oxidative stress, hyperproliferative response and necrosis. In oxidative stress protection studies, the decrease in the level of renal glutathione and antioxidant enzyme activities induced by Fe-NTA were significantly reversed by GTN pretreatment in a dose-dependent manner (12-46% recovery, P<0.05-0.001). GTN pretreatment also resulted in a dose-dependent inhibition (24-39% inhibition, P<0.05-0.001) of Fe-NTA-induced lipid peroxidation as measured by TBARS formation in renal tissues. Similarly, in hyperproliferation protection studies, GTN pretreatment showed a strong inhibition of Fe-NTA-induced renal ornithine decarboxylase (ODC) activity (51-57% inhibition, P<0.001) and [3H]thymidine incorporation (43-58% inhibition, P<0.001) into renal DNA. GTN pretreatment almost completely prevented kidney biomolecules from oxidative damage and protected the tissue against the observed histopathological alterations. From this data, it can be concluded that exogenously produced NO from GTN might scavenge reactive oxygen species (ROS) and decreases toxic metabolites of Fe-NTA and thereby inhibiting renal oxidative stress. In addition, exogenously produced NO can also inhibit Fe-NTA-induced hyperproliferative response by down-regulating the activity of ODC and the rate of [3H]thymidine incorporation into renal DNA and could be suggested as another possible clinical application for this NO-donor (GTN, traditionally used as a vasodilator) in oncological medicine.

• Authors: Mohammad Iqbal, Yasumasa Okazaki, Som Datta Sharma, Shigeru Okada
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1623 Issue 2-3 Pg. 98-108 (Oct 13 2003) ISSN: 0006-3002 [Print] Netherlands
• PMID: 14572907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Ferric Compounds
• Nitric Oxide Donors
• Ornithine Decarboxylase Inhibitors
• Nitric Oxide
• DNA
• Ornithine Decarboxylase
• Nitroglycerin
• Glutathione
• Nitrilotriacetic Acid
• ferric nitrilotriacetate

Topics

• Animals
• Antioxidants (metabolism)
• Cell Division (drug effects)
• DNA (biosynthesis)
• Ferric Compounds (toxicity)
• Glutathione (metabolism)
• Kidney (drug effects, metabolism, pathology)
• Lipid Peroxidation (drug effects)
• Male
• Mice
• Necrosis
• Nitric Oxide (metabolism)
• Nitric Oxide Donors (pharmacology)
• Nitrilotriacetic Acid (analogs & derivatives, toxicity)
• Nitroglycerin (pharmacology)
• Ornithine Decarboxylase (biosynthesis)
• Ornithine Decarboxylase Inhibitors
• Oxidative Stress