title: Arginine and asymmetric dimethylarginine in puromycin aminonucleoside-induced chronic kidney disease in the rat.
abstract: OBJECTIVE
  Reduced renal L-arginine (L-Arg) synthesis/transport, induction of arginases and increased endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) will inhibit NO production. This study investigated pathways of L-Arg synthesis/uptake/utilization, ADMA degradation and oxidant/antioxidants in puromycin aminonucleoside (PAN) chronic kidney disease (CKD).
  
  
  METHODS
  Rats were given low- (LD) or high-dose (HD) PAN and followed for 11 weeks for proteinuria. BP was measured and blood and tissues were harvested and analyzed for abundance of argininosuccinate synthase (ASS) and lyase (ASL), arginase, cationic amino acid transporter (CAT1) and dimethylargininedimethylaminohydrolase (DDAH) in kidney, cortex, aorta and liver. Arginase and DDAH activity, plasma L-Arg and ADMA, renal pathology and creatinine clearances were also measured.
  
  
  RESULTS
  PAN caused dose-dependent kidney damage and hypertension and creatinine clearance fell in HD-PAN. Renal ASS fell in HD-PAN, renal cortex and aortic ASL and membrane CAT1 fell in both PAN groups. There was no activation of renal arginase, but aortic arginase increased in LD-PAN. Renal DDAH activity fell moderately in LD-PAN and markedly in HD-PAN where hepatic DDAH activity also fell. Plasma L-Arg was unchanged while ADMA rose moderately and dose-dependently with PAN. There were several indices of oxidative stress which was most prominent in HD-PAN.
  
  
  CONCLUSIONS
  Reduction in renal ASS/ASL and loss of renal cortex CAT1 compromises renal L-Arg synthesis and release. Loss of aortic CAT1 impairs L-Arg uptake. Increased plasma ADMA was associated with progressive loss of renal DDAH activity. However, loss of renal clearance and falls in hepatic DDAH activity in HD-PAN did not have additive effects on plasma ADMA.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, USA.
authors.forename: Gin-Fu
authors.initials: GF
authors.lastname: Chen
authors.forename: Natasha C
authors.initials: NC
authors.lastname: Moningka
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sasser
authors.forename: Sergey
authors.initials: S
authors.lastname: Zharikov
authors.forename: Mark
authors.initials: M
authors.lastname: Cunningham
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
authors.forename: Idit F
authors.initials: IF
authors.lastname: Schwartz
authors.forename: Chris
authors.initials: C
authors.lastname: Baylis
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001119:Arginase / Q000097:blood; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D007672:Kidney Cortex / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000097:blood*; D008297:Male; D018384:Oxidative Stress; D011692:Puromycin Aminonucleoside / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011692:Puromycin Aminonucleoside; C018524:N,N-dimethylarginine; D001120:Arginine; D003404:Creatinine; D001119:Arginase