title: Atorvastatin inhibits renal crystal retention in a rat stone forming model.
abstract: OBJECTIVE
  The interactions between crystals and renal tubular cells are important factors in urolithiasis formation. Moreover, some reports have suggested the involvement of renal tubular cell injury in crystal-cell interaction processes. Atorvastatin, which is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, is prescribed to decrease high cholesterol levels, and it has anti-inflammation and anti-oxidization activities. Atorvastatin is also reported to control transforming growth factor-beta1 expression. We investigated whether atorvastatin can prevent renal tubular cell injury by oxalate and inhibit renal crystal retention.
  
  
  METHODS
  Ten-week-old specific pathogen-free male Sprague-Dawley rats were used. Atorvastatin (2 mg/kg) in 0.5% carboxymethyl cellulose was administered orally daily for 2 weeks. The rats were separated into 4 experimental groups, including group 1--water and 0.5% carboxymethyl cellulose daily, group 2--water and atorvastatin in 0.5% carboxymethyl cellulose daily, group 3--1% ethylene glycol dissolved in water, 0.5 mug vitamin D3 dissolved in 1 ml salad oil and 0.5% carboxymethyl cellulose daily, and group 4--1% ethylene glycol dissolved in water, 0.5 microg vitamin D3 dissolved in 1 ml salad oil and atorvastatin in 0.5% carboxymethyl cellulose daily. The ethylene glycol model of hyperoxaluria and the effect of atorvastatin treatment were analyzed in groups 1 to 4. Urine samples were collected every 24 hours in metabolic cages and analyzed immediately or stored at -70C until analysis. The rats were sacrificed after 2 weeks and the kidneys were removed for further examination. We measured urinary N-acetyl glucosaminidase levels as a biomarker of renal tubular cell injury and urinary 8-OHdG as a biomarker of oxidative stress in 24-hour urine samples. Removed kidneys were used for quantitative analysis of the superoxide dismutase level and the detection of apoptosis. Finally, we measured the amount of crystal deposits in renal tubular cells.
  
  
  RESULTS
  Urinary N-acetyl glucosaminidase and 8-OHdG levels were decreased significantly by atorvastatin treatment in this stone forming rat model. Atorvastatin treatment increased the superoxide dismutase level and inhibited the degree of renal tubular cell N-acetyl glucosaminidase compared with stone forming control group 3. A decrease in renal crystal retention was noted when excised kidneys were evaluated following atorvastatin treatment.
  
  
  CONCLUSIONS
  Atorvastatin was found to have inhibitory effects on the renal tubular cell injury and oxidative stress caused by oxalate and crystals. Atorvastatin inhibited renal crystal retention. We believe that atorvastatin could help prevent and treat renal crystal formation.
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan. tsujihata@uro.med.osaka-u.ac.jp
authors.forename: Masao
authors.initials: M
authors.lastname: Tsujihata
authors.forename: Chikahiro
authors.initials: C
authors.lastname: Momohara
authors.forename: Iwao
authors.initials: I
authors.lastname: Yoshioka
authors.forename: Akira
authors.initials: A
authors.lastname: Tsujimura
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000069059:Atorvastatin; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D007669:Kidney Calculi / Q000188:drug therapy* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010070:Oxalates / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011336:Probability; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D013482:Superoxide Dismutase / Q000378:metabolism*; D016482:Urinalysis
chemical_list: D006538:Heptanoic Acids; D010070:Oxalates; D011758:Pyrroles; D000069059:Atorvastatin; D013482:Superoxide Dismutase