Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model

• Published in: Renal failure Vol. 39; no. 1; pp. 629 - 642
• Main Authors: Thomsen, Lise Høj, Fog-Tonnesen, Morten, Nielsen Fink, Lisbeth, Norlin, Jenny, García de Vinuesa, Amaya, Hansen, Troels Krarup, de Heer, Emile, ten Dijke, Peter, Rosendahl, Alexander
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.11.2017; Taylor & Francis Ltd
• Subjects: Adult; Aged; Aged, 80 and over; Animals; BMP; Bone morphogenetic proteins; Bone Morphogenetic Proteins - antagonists & inhibitors; Bone Morphogenetic Proteins - metabolism; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - pathology; Diabetic Nephropathies - etiology; Diabetic Nephropathies - pathology; diabetic nephropathy; Disease Models, Animal; Female; Fibrosis; Glycoproteins - metabolism; Humans; Intercellular Signaling Peptides and Proteins - metabolism; kidney; Kidney Glomerulus - pathology; Kidney Tubules - pathology; Kidneys; Laboratory Study; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular modelling; mRNA; Nephropathy; Phosphorylation; Receptors, Leptin - genetics; RNA, Messenger - metabolism; Signal Transduction; Smad protein; Smad2 protein; Smad2 Protein - metabolism; SOST protein; TGF-β; Transforming Growth Factor beta1; Transforming growth factor-b; Tubules; Type 2 diabetes; Up-Regulation; Type 2 diabetes; kidney; TGF-β; fibrosis; BMP; diabetic nephropathy
• ISSN: 0886-022X; 1525-6049
• DOI: 10.1080/0886022X.2017.1361837

Uncontrolled activation of transforming growth factor beta (TGF-β) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DN). We evaluated and compared downstream activation of the Smad2-signaling pathway in kidney samples from T2D patients to kidneys from the T2D model of leptin receptor deficient db/db mouse. Furthermore, expression of TGF-β family members was evaluated to elucidate molecular mechanisms in the mouse model. Kidney samples from patients with advanced stages of DN showed elevated pSmad2 staining whereas db/db mouse kidneys surprisingly showed a decrease in pSmad2 in the tubular compartment. Structurally, kidney tissue showed dilated tubules and expanded glomeruli, but no clear fibrotic pattern was found in the diabetic mice. Selective TGF-β family members were up-regulated at the mRNA level. Antagonists of bone morphogenetic protein (BMP) ligands, such as Gremlin1, USAG1 and Sclerostin, were strongly up-regulated suggesting a dampening effect on BMP pathways. Together, these results indicate a lack of translation from T2D patient kidneys to the db/db model with regards to Smad signaling pathway. It is plausible that a strong up-regulation of BMP antagonizing factors account for the lack of Smad1/5/8 activation, in spite of increased expression of several BMP members.