期刊
RENAL FAILURE
卷 39, 期 1, 页码 629-642出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/0886022X.2017.1361837
关键词
Type 2 diabetes; diabetic nephropathy; fibrosis; TGF-beta; BMP; kidney
资金
- Dutch association of arthritis Reumafonds
Uncontrolled activation of transforming growth factor beta (TGF-beta) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DIN). 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-beta 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-beta 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.
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