title: Ureic clearance granule, alleviates renal dysfunction and tubulointerstitial fibrosis by promoting extracellular matrix degradation in renal failure rats, compared with enalapril.
abstract: BACKGROUND
  Chinese herbal compound prescription has a unique therapeutic action on chronic kidney disease (CKD) in China. In clinics, Uremic Clearance Granules (UCG), a compounded Chinese patent medicine, has been frequently used to treat chronic renal failure (CRF) patients for nearly 30 years, however, the deep therapeutic mechanisms involved in vivo remain a challenge. This study aims to demonstrate the effects and mechanisms of UCG on renal dysfunction and tubulointerstitial fibrosis by regulating extracellular matrix (ECM) degradation and transforming growth factor (TGF)-beta1/Smad signaling activity in vivo, compared with enalapril.
  
  
  METHODS
  Twenty-six rats were randomly divided into 4 groups, a sham-operated group (Sham group), a vehicle-intervened group (Vehicle group), a UCG-treated group (UCG group) (5g/kg/day) and an enalapril-treated group (Enalapril group) (20mg/kg/day). The rats with renal failure were induced by adenine (150 mg/kg/day) and unilateral ureteral obstruction (UUO), and killed on day 35 after the administration. Proteinuria, urinary N-acetyl-beta-D-glucosaminidase (UNAG), blood biochemical parameters, renal morphological changes, collagen type IV (CIV), matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors of metalloproteinase (TIMP)-1, as well as the key molecular protein expressions in TGF-beta1/Smad signaling pathway were observed, respectively.
  
  
  RESULTS
  Adenine administration and UUO induced severe renal damages, as indicated by renal dysfunction, proteinuria and the marked histopathological injuries in the tubules and interstitium, which were associated with MMP-2/TIMP-1 imbalance and TGF-beta1/Smad signaling activity, as shown by up-regulation of the protein expressions of TGF-beta1, TGF-beta receptor type I (RI), TGF-beta receptor type II (RII), Smad2/3, phosphorylated-Smad2/3 (p-Smad2/3) and Smad4, as well as down-regulation of the protein expression of Smad7 in the kidney. UCG treatment, however, significantly not only attenuated renal dysfunction and tubulointerstitial fibrosis, but also improved the protein expressions of MMP-2, TIMP-1, TGF-beta1, TGF-beta RI, p-Smad2/3, Smad4 and Smad7 in the kidney. Besides, the effects of UCG were stronger than those of enalapril partly.
  
  
  CONCLUSIONS
  UCG similar to enalapril, is renoprotective via ameliorating renal dysfunction and tubulointerstitial fibrosis in the renal failure model. The potential mechanisms by which UCG exerts its therapeutical effects in vivo are through promoting ECM degradation and regulating MMP-2/TIMP-1 balance or signaling molecular activity in TGF-beta1/Smad pathway in the kidney. These findings suggest that UCG treatment is undoubtedly useful in preventing the progression of CRF.
authors.affiliation: Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjng, China.
authors.forename: Yan-Ru
authors.initials: YR
authors.lastname: Huang
authors.affiliation: Changshu Hospital of Traditional Chinese Medicine, Changshu, China.
authors.forename: Qing-Xue
authors.initials: QX
authors.lastname: Wei
authors.affiliation: Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China. Electronic address: wyg68918@sina.com.
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Wan
authors.affiliation: Department of Nephrology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing 210029, Nanjing, China. Electronic address: wyg68918@hotmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjng, China.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Mao
authors.affiliation: Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjng, China.
authors.forename: Hao-Li
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjng, China.
authors.forename: Xian-Jie
authors.initials: XJ
authors.lastname: Meng
authors.affiliation: Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjng, China.
authors.forename: Xi-Miao
authors.initials: XM
authors.lastname: Shi
authors.affiliation: Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjng, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Guangzhou Consun Drug Research Ltd., Guangzhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D005109:Extracellular Matrix / Q000187:drug effects; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000652:urine; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D004365:Drugs, Chinese Herbal; D020011:Protective Agents; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C000600254:niaoduqing keli; D004656:Enalapril; D000118:Acetylglucosaminidase
keywords: Extracellular matrix degradation; Matrix metalloproteinases; Renal dysfunction; TGF‐beta1/Smad signaling; Tubulointerstitial fibrosis; Uremic Clearance Granules