title: Benazepril affects integrin-linked kinase and smooth muscle α-actin expression in diabetic rat glomerulus and cultured mesangial cells.
abstract: BACKGROUND
  Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and is associated with excessive cardiovascular morbidity and mortality. The angiotensin converting enzyme inhibitor (ACEI) benazepril has been shown to slow the progression of chronic renal disease and have beneficial effects in patients with a combination of chronic renal disease and cardiovascular disease. Transforming growth factor-β(1) (TGF-β(1)) plays a central role in the pathogenesis and progression of DN. Integrin-linked kinase (ILK) can modulate TGF-β(1)-induced glomerular mesangial cell (GMC) injury, which is a prominent characteristic of renal pathology in kidney diseases. As an integrin cytoplasmic-binding protein, ILK regulates fibronectin (FN) matrix deposition and the actin cytoskeleton. Smooth muscle α-actin (α-SMA) is involved in progressive renal dysfunction in both human and experimental renal disease.
  
  
  METHODS
  To explore the mechanisms of benazepril's reno-protective effects, we examined the expression of TGF-β(1), ILK, and α-SMA in GMC exposed to high glucose (HG) and in the kidneys of streptozotocin (STZ)-induced diabetic rats using real-time quantitative RT-PCR and western blot analysis. To elucidate the mechanism(s) of the effect of benazepril on GMC cellular processes, we assessed the effect of benazepril on Angiotensin II (Ang II) signalling pathways using western blot analysis.
  
  
  RESULTS
  The expression of TGF-β(1), ILK, and α-SMA increased significantly in the diabetic group compared with the control group. Benazepril treatment inhibited the expression of these genes in DN but failed to rescue the same levels in the control group. Similar results were found in GMC treated with HG or benazepril. Ang II increased ERK and Akt phosphorylation in the HG group, and benazepril could not completely block these responses, suggesting that other molecules might be involved in the progression of DN. Our findings suggest that benazepril decreases ILK and α-SMA expression, at least in part, by affecting the interactions between Ang II and TGF-β(1).
  
  
  CONCLUSIONS
  The findings described here support the hypothesis that the HG milieu of diabetes increases TGF-β(1) secretion, which increases the synthesis of ILK and α-SMA that are involved in the progression of DN. This might be an important mechanism of the benazepril renal-protective function in the pathogenesis of DN.
authors.forename: Honglin
authors.initials: H
authors.lastname: Niu
authors.forename: Lei
authors.initials: L
authors.lastname: Nie
authors.forename: Maodong
authors.initials: M
authors.lastname: Liu
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Chi
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China. liyinghebei@126.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D000099200:Scaffold Protein ILK
chemical_list: D000199:Actins; D001552:Benzazepines; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C044946:benazepril