title: Atorvastatin improves pathological changes in the aged kidney by upregulating peroxisome proliferator-activated receptor expression and reducing matrix metalloproteinase-9 and transforming growth factor-β1 levels.
abstract: OBJECTIVE
  To investigate the effects of atorvastatin (AVT) on renal function and renal pathological changes in the aged rat and explore their possible mechanisms.
  
  
  METHODS
  Twenty-month-old, normal female Wistar rats were divided into three groups: group A (n=8) was fed high-dose AVT (10mg/kg/d); group B (n=8) was fed low-dose AVT (1mg/kg/d); and group C (controls, n=8) received the same volume of normal saline; 3-month-old, normal female Wistar rats served as young normal controls (n=8). All rats were sacrificed following a 4-month treatment period. Serum creatinine and blood lipid levels were measured. The glomerular sclerosis index and tubulointerstitial lesions were determined using renal periodic acid-Schiff-stained paraffin sections. The mRNA and protein expressions of matrix metalloproteinases (MMP)-9 and -2, tissue inhibitors of metalloproteinase (TIMP)-1 and -2, transforming growth factor-β1 (TGF-β1), and peroxisome proliferator-activated receptors (PPARs) were examined using reverse transcription polymerase chain reactions and Western blots, respectively.
  
  
  RESULTS
  Serum lipid (including serum cholesterol and serum triglycerides) levels in aged rats were significantly higher than those in young rats (p<0.05). Compared to the aged control group, high-dose AVT was associated with significantly lower serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels in aged rats (p<0.05); low-dose AVT was associated only with lower serum LDL-C levels (p<0.05). Renal morphological changes in aged rats included focal glomerulosclerosis, infiltration of inflammatory cells, and arteriole sclerosis. Improved renal pathology was observed in aged, AVT-treated rats, and included a decreased glomerular sclerosis index and tubulointerstitial lesion score, especially in those receiving high-dose AVT. Additionally, renal artery wall thickening, luminal narrowing, and arteriolosclerosis were significantly less severe in aged rats receiving high-dose AVT. Upregulated expression of MMP-9 and TGF-β1 was observed in the renal tissue of aged rats. AVT treatment was associated with a reversal of these phenomena and upregulated expression of TIMP-1, PPARα, PPARβ, and PPARγ in aged rats.
  
  
  CONCLUSIONS
  AVT improved the renal pathology of aged rats. These effects may have been induced by the lowering of blood lipids, maintaining the MMP/TIMP balance, and downregulating the expression of TGF-β1. AVT may reduce the levels of MMP-9 and TGF-β in aged rats by upregulating the expression of PPARs.
authors.affiliation: Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: qlcheng64@163.com.
authors.forename: Qingli
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: yeping@sina.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.affiliation: Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Qiangguo
authors.initials: Q
authors.lastname: Ao
authors.affiliation: Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Geriatric Medicine, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yazuo
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000367:Age Factors; D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D001284:Atrophy; D015536:Down-Regulation; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008055:Lipids / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D000069059:Atorvastatin; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: Aged rats; Atorvastatin; Kidney; Pathology