title: Renoprotective effects of melatonin in young spontaneously hypertensive rats with L-NAME.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Ming-Chou
authors.initials: MC
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Ting-Hsin
authors.initials: TH
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Li-Tung
authors.initials: LT
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: tainyl@hotmail.com.
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000517:prevention & control; D006977:Hypertension, Renal / Q000378:metabolism / Q000517:prevention & control*; D007668:Kidney / Q000201:enzymology*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D009393:Nephritis / Q000378:metabolism / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D000975:Antioxidants; C026512:arginine methyl ester; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase; D003849:Deoxyguanosine; D008550:Melatonin; D019331:NG-Nitroarginine Methyl Ester
keywords: asymmetric dimethylarginine; hypertension; kidney disease; melatonin; nitric oxide; oxidative stress