Jiahui Zhao1, Qingli Cheng2, Ping Ye3, Guang Yang1, Sheng Liu1, Qiangguo Ao1, Yang Liu1, Yazuo Hu4. 1. Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing 100853, China. 2. Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: qlcheng64@163.com. 3. Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: yeping@sina.com. 4. Institute of Geriatric Medicine, Chinese PLA General Hospital, Beijing 100853, China.
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. CONCLUSION: 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.
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. CONCLUSION: 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.