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Renoprotective effects of melatonin in young spontaneously hypertensive rats with L-NAME.

AbstractBACKGROUND:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSION:
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.
AuthorsMing-Chou Cheng, Ting-Hsin Wu, Li-Tung Huang, You-Lin Tain
JournalPediatrics and neonatology (Pediatr Neonatol) Vol. 55 Issue 3 Pg. 189-95 (Jun 2014) ISSN: 2212-1692 [Electronic] Singapore
PMID24268813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013. Published by Elsevier B.V.
Chemical References
  • Antioxidants
  • arginine methyl ester
  • Nitric Oxide
  • N,N-dimethylarginine
  • 8-Hydroxy-2'-Deoxyguanosine
  • Arginine
  • Nitric Oxide Synthase
  • Amidohydrolases
  • dimethylargininase
  • Deoxyguanosine
  • Melatonin
  • NG-Nitroarginine Methyl Ester
Topics
  • 8-Hydroxy-2'-Deoxyguanosine
  • Amidohydrolases (metabolism)
  • Animals
  • Antioxidants (pharmacology)
  • Arginine (analogs & derivatives, metabolism)
  • Blood Pressure (drug effects)
  • Deoxyguanosine (analogs & derivatives)
  • Humans
  • Hypertension (metabolism, prevention & control)
  • Hypertension, Renal (metabolism, prevention & control)
  • Kidney (enzymology)
  • Male
  • Melatonin (pharmacology)
  • NG-Nitroarginine Methyl Ester (toxicity)
  • Nephritis (metabolism, prevention & control)
  • Nitric Oxide (metabolism)
  • Nitric Oxide Synthase (metabolism)
  • Rats
  • Rats, Inbred SHR

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