cyclic-gmp and 1-3-dimethylthiourea

We examined the role of oxygen free radicals in cisplatin-induced acute renal failure (ARF). The intravenous injection of cisplatin (5 mg/kg body weight) induced an increase in serum creatinine and tubular damage in the outer stripe of the outer medulla in rats. The renal content of malondialdehyde (MDA) transiently increased. Treatment with the free radical scavengers dimethylthiourea (DMTU) or lecithinized superoxide dismutase (L-SOD) attenuated the increase in serum creatinine. The beneficial effect of DMTU, a hydroxyl radical scavenger, was associated with less accumulation of MDA, less tubular damage, and enhanced expression of proliferating cell nuclear antigen (PCNA) in the damaged tubular cells, but not with improvement of reduced renal blood flow (RBF). On the other hand, the beneficial effect of L-SOD, a superoxide anion scavenger, was associated with preservation of RBF and increased urinary guanosine 3',5'-cyclic monophosphate excretion but not with modification of tubular damage or PCNA expression. These results suggest that (1) cisplatin-induced nephrotoxicity was associated with lipid peroxidation, (2) the hydroxyl radical scavenger prevented ARF through both attenuation of tubular damage and enhanced regenerative response of the damaged tubular cells, and (3) the superoxide anion scavenger did the same through preservation of RBF. It follows that oxygen free radicals may play an important role in cisplatin-induced ARF by reducing RBF and inducing tubular damage.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Animals; Cisplatin; Creatinine; Cyclic GMP; Free Radical Scavengers; Kidney Tubules; Lipid Peroxidation; Male; Malondialdehyde; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Renal Circulation; Superoxide Dismutase; Thiourea

Studies were performed to examine the mechanisms for the protective effects of free radical scavengers on gentamicin (GM)-mediated nephropathy. Administration of GM at 40 mg/kg sc for 13 days to rats induced a significant reduction in renal blood flow (RBF) and inulin clearance (CIn) as well as marked tubular damage. A significant reduction in urinary guanosine 3',5'-cyclic monophosphate (cGMP) excretion and a significant increase in renal cortical renin and endothelin-1 contents were also observed in GM-mediated nephropathy. Superoxide dismutase (SOD) or dimethylthiourea (DMTU) significantly lessened the GM-induced decrement in CIn. The SOD-induced increase in glomerular filtration rate was associated with a marked improvement in RBF, an increase in urinary cGMP excretion, and a decrease in renal renin and endothelin-1 content. SOD did not attenuate the tubular damage. In contrast, DMTU significantly reduced the tubular damage and lipid peroxidation, but it did not affect renal hemodynamics and vasoactive substances. Neither SOD nor DMTU affected the renal cortical GM content in GM-treated rats. These results suggest that 1) both SOD and DMTU have protective effects on GM-mediated nephropathy, 2) the mechanisms for the protective effects differ for SOD and DMTU, and 3) superoxide anions play a critical role in GM-induced renal vasoconstriction.

Topics: Acetylglucosaminidase; Animals; Cyclic GMP; Endothelins; Free Radical Scavengers; Gentamicins; Kidney; Kidney Diseases; Lipid Peroxides; Male; Rats; Rats, Sprague-Dawley; Renal Circulation; Renin; Superoxide Dismutase; Thiourea