BAMBI elimination enhances alternative TGF-beta signaling and glomerular dysfunction in diabetic mice

Autor: Jia Fu, Nicolas Guillot, John Cijiang He, Maja T. Lindenmeyer, Xuezhu Li, Niansong Wang, Kyung Lee, Clemens D. Cohen, Peter Y. Chuang, Wenzhen Xiao, Ying Fan, Raymond C. Harris, Margaret H. Baron, Detlef Schlöndorff
Přispěvatelé: Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)
Jazyk: angličtina
Rok vydání: 2015
Předmět:
MAPK/ERK pathway
medicine.medical_specialty
Complications
Endocrinology
Diabetes and Metabolism
[SDV]Life Sciences [q-bio]
Kidney Glomerulus
Transforming Growth Factor beta/*metabolism
Smad5 Protein/genetics/metabolism
In Vitro Techniques
Diabetic nephropathy
Mice
Downregulation and upregulation
Transforming Growth Factor beta
Internal medicine
Internal Medicine
medicine
Humans
Animals
Endothelial dysfunction
Membrane Proteins/genetics/*metabolism
biology
Chemistry
Blotting
Signal Transduction/physiology
MEK inhibitor
Vascular Endothelial Growth Factor Receptor-2/genetics/metabolism
Membrane Proteins
Kinase insert domain receptor
Transforming growth factor beta
Kidney Glomerulus/*metabolism/pathology
medicine.disease
Angiopoietin-1/genetics/metabolism
3. Good health
Cell biology
Endocrinology
Smad1 Protein/genetics/metabolism
biology.protein
BAMBI
Western
Zdroj: Diabetes
Diabetes, American Diabetes Association, 2015, 64 (6), pp.2220-33. ⟨10.2337/db14-1397⟩
ISSN: 0012-1797
DOI: 10.2337/db14-1397⟩
Popis: International audience; BMP, activin, membrane-bound inhibitor (BAMBI) acts as a pseudo-receptor for the transforming growth factor (TGF)-beta type I receptor family and a negative modulator of TGF-beta kinase signaling, and BAMBI(-/-) mice show mild endothelial dysfunction. Because diabetic glomerular disease is associated with TGF-beta overexpression and microvascular alterations, we examined the effect of diabetes on glomerular BAMBI mRNA levels. In isolated glomeruli from biopsies of patients with diabetic nephropathy and in glomeruli from mice with type 2 diabetes, BAMBI was downregulated. We then examined the effects of BAMBI deletion on streptozotocin-induced diabetic glomerulopathy in mice. BAMBI(-/-) mice developed more albuminuria, with a widening of foot processes, than BAMBI(+/+) mice, along with increased activation of alternative TGF-beta pathways such as extracellular signal-related kinase (ERK)1/2 and Smad1/5 in glomeruli and cortices of BAMBI(-/-) mice. Vegfr2 and Angpt1, genes controlling glomerular endothelial stability, were downmodulated in glomeruli from BAMBI(-/-) mice with diabetes. Incubation of glomeruli from nondiabetic BAMBI(+/+) or BAMBI(-/-) mice with TGF-beta resulted in the downregulation of Vegfr2 and Angpt1, effects that were more pronounced in BAMBI(-/-) mice and were prevented by a MEK inhibitor. The downregulation of Vegfr2 in diabetes was localized to glomerular endothelial cells using a histone yellow reporter under the Vegfr2 promoter. Thus, BAMBI modulates the effects of diabetes on glomerular permselectivity in association with altered ERK1/2 and Smad1/5 signaling. Future therapeutic interventions with inhibitors of alternative TGF-beta signaling may therefore be of interest in diabetic nephropathy.
Databáze: OpenAIRE
Externí odkaz: