8-hydroxy-2--deoxyguanosine and Hypertension--Renal

Nitric oxide (NO) deficiency occurs in humans and animals with hypertension and chronic kidney disease (CKD). An inhibitor of NO synthase, N(G)-nitro-l-arginine methyl ester (L-NAME) exacerbates kidney damage in the adult spontaneously hypertensive rat (SHR). We examined whether L-NAME exacerbated hypertensive nephrosclerosis in young SHRs and whether melatonin protects SHRs against kidney damage by restoration of the asymmetric dimethylarginine (ADMA)-NO pathway.. Rats aged 4 weeks were randomly assigned into three groups (n = 10 for each group): Group 1 (control), SHRs without treatment; Group 2 (L-NAME), SHRs received L-NAME (80 mg/L) in drinking water; and Group 3 (L-NAME + melatonin), SHRs received L-NAME (80 mg/L) and 0.01% melatonin in drinking water. All rats were sacrificed at 10 weeks of age.. L-NAME exacerbates the elevation of blood pressure, renal dysfunction, and glomerular sclerosis in young SHRs. L-NAME induced an increase of ADMA and a decrease of arginine-to-ADMA ratio in the SHR kidney. Melatonin therapy prevented L-NAME-exacerbated hypertension and nephrosclerosis in young SHRs. In addition, melatonin restored L-NAME-induced reduction of dimethylarginine dimethylaminohydrolase (DDAH; ADMA-metabolizing enzymes) activity in the SHR kidney. Next, melatonin decreased renal ADMA concentrations, increased renal arginine-to-ADMA ratio, and restored NO production in L-NAME-treated young SHRs. Moreover, melatonin reduced the degree of oxidative damaged DNA product, 8-hydroxydeoxyguanosine immunostaining in L-NAME-treated SHR kidney.. Our results indicated that L-NAME/SHR is a useful model for hypertensive nephrosclerosis in young rats. The blood pressure-lowering and renoprotective effects of melatonin is due to increases of DDAH activity, decreases of ADMA, and reduction of oxidative stress in L-NAME-treated SHR kidney. Specific therapy targeting the DDAH-ADMA pathway may be a promising approach to slowing chronic kidney disease progression in children.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amidohydrolases; Animals; Antioxidants; Arginine; Blood Pressure; Deoxyguanosine; Humans; Hypertension; Hypertension, Renal; Kidney; Male; Melatonin; Nephritis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Inbred SHR

The presence of hypertension increases renal oxidative stress by increasing NADPH oxidase-dependent superoxide production and by decreasing antioxidant defense in the early stage of experimental diabetes mellitus (DM). In the present study, we investigated whether the administration of an antioxidant mimetic of the superoxide dismutase (SOD) (tempol) corrects the oxidative imbalance and oxidative stress-induced renal injury in the presence of DM and hypertension.. DM was induced in spontaneously hypertensive rats (SHR) by streptozotocin at 4 weeks of age. The diabetic rats either did or did not receive tempol for 20 days. Oxidative-stress parameters and indices of renal injury were evaluated.. Tempol reestablished the imbalance in redox status induced by DM. It elevated the expression of renal antioxidant extracellular SOD, p < 0.0001; decreased (p = 0.049) the production of renal NADPH-dependent superoxide production, and diminished (p = 0.016) a marker of oxidative stress-induced DNA damage, 8-hydroxy-2'-deoxyguanosine. Reduction of oxidative stress markers was associated with reduction in renal damage parameters associated with DN. DM-induced albuminuria and elevation in renal expression of collagen IV were reduced to the level observed in control rats.. We conclude that an imbalance in renal redox status is associated with markers of renal injury in the early stage of DM and hypertension. Antioxidant treatment reestablished the redox status and prevented oxidative stress-induced renal damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Collagen Type IV; Cyclic N-Oxides; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Progression; Hypertension, Renal; Kidney; Male; Molecular Mimicry; NADPH Oxidases; Oxidative Stress; Rats; Rats, Inbred SHR; Spin Labels; Superoxide Dismutase