title: Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice.
abstract: OBJECTIVE
  Brain natriuretic peptide (BNP) is a potent vasorelaxing and natriuretic peptide that is secreted from the heart and has cardioprotective properties. We have previously generated hypotensive transgenic mice (BNP-Tg mice) that overproduce BNP in the liver, which is released into the circulation. Using this animal model, we successfully demonstrated the amelioration of renal injury after renal ablation and in proliferative glomerulonephritis. Glomerular hyperfiltration is an early haemodynamic derangement, representing one of the key mechanisms of the pathogenesis of diabetic nephropathy. Based on the suggested involvement of increased endogenous natriuretic peptides, the aim of this study was to investigate their role in the development and progression of diabetic nephropathy.
  
  
  METHODS
  We evaluated the progression of renal injury and fibrogenesis in BNP-Tg mice with diabetes induced by streptozotocin. We also investigated the effect of BNP on high glucose-induced signalling abnormalities in mesangial cells.
  
  
  RESULTS
  After induction of diabetes, control mice exhibited progressively increased urinary albumin excretion with impaired renal function, whereas these changes were significantly ameliorated in BNP-Tg mice. Notably, diabetic BNP-Tg mice revealed minimal mesangial fibrogenesis with virtually no glomerular hypertrophy. Glomerular upregulation of extracellular signal-regulated kinase, TGF-beta and extracellular matrix proteins was also significantly inhibited in diabetic BNP-Tg mice. In cultured mesangial cells, activation of the above cascade under high glucose was abrogated by the addition of BNP.
  
  
  CONCLUSIONS
  Chronic excess of BNP prevents glomerular injury in the setting of diabetes, suggesting that renoprotective effects of natriuretic peptides may be therapeutically applicable in preventing the progression of diabetic nephropathy.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Makino
authors.forename: M
authors.initials: M
authors.lastname: Mukoyama
authors.forename: K
authors.initials: K
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Suganami
authors.forename: M
authors.initials: M
authors.lastname: Kasahara
authors.forename: K
authors.initials: K
authors.lastname: Yahata
authors.forename: T
authors.initials: T
authors.lastname: Nagae
authors.forename: H
authors.initials: H
authors.lastname: Yokoi
authors.forename: K
authors.initials: K
authors.lastname: Sawai
authors.forename: Y
authors.initials: Y
authors.lastname: Ogawa
authors.forename: S
authors.initials: S
authors.lastname: Suga
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshimasa
authors.forename: A
authors.initials: A
authors.lastname: Sugawara
authors.forename: I
authors.initials: I
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D005920:Glomerular Mesangium / Q000502:physiology; D005921:Glomerulonephritis / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D020097:Natriuretic Peptide, Brain / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D012333:RNA, Messenger; D020097:Natriuretic Peptide, Brain; D012313:RNA