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Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats.

ABSTRACT: Prior study shows that maternal protein-restricted (LP) 16-wk-old offspring have pronounced reduction of nephron number and arterial hypertension associated with unchanged glomerular filtration rate, besides enhanced glomerular area, which may be related to glomerular hyperfiltration/overflow and which accounts for the glomerular filtration barrier breakdown and early glomerulosclerosis. In the current study, LP rats showed heavy proteinuria associated with podocyte simplification and foot process effacement. TGF-?1 glomerular expression was significantly enhanced in LP. Isolated LP glomeruli show a reduced level of miR-200a, miR-141, miR-429 and ZEB2 mRNA and upregulated collagen 1?1/2 mRNA expression. By western blot analyzes of whole kidney tissue, we found significant reduction of both podocin and nephrin and enhanced expression of mesenchymal protein markers such as desmin, collagen type I and fibronectin. From our present knowledge, these are the first data showing renal miRNA modulation in the protein restriction model of fetal programming. The fetal-programmed adult offspring showed pronounced structural glomerular disorders with an accentuated and advanced stage of fibrosis, which led us to state that the glomerular miR-200 family would be downregulated by TGF-?1 action inducing ZEB 2 expression that may subsequently cause glomeruli epithelial-to-mesenchymal transition.

SUBMITTER: Sene Lde B

PROVIDER: S-EPMC3747155 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats.

Sene Letícia de Barros Lde B Mesquita Flávia Fernandes FF de Moraes Leonardo Nazário LN Santos Daniela Carvalho DC Carvalho Robson R Carvalho Robson R Gontijo José Antônio Rocha JA Boer Patrícia Aline PA

PloS one 20130819 8

Prior study shows that maternal protein-restricted (LP) 16-wk-old offspring have pronounced reduction of nephron number and arterial hypertension associated with unchanged glomerular filtration rate, besides enhanced glomerular area, which may be related to glomerular hyperfiltration/overflow and which accounts for the glomerular filtration barrier breakdown and early glomerulosclerosis. In the current study, LP rats showed heavy proteinuria associated with podocyte simplification and foot proce ...[more]

PMID: 23977013

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Project description:Trimetazidine (TMZ), as a metabolic regulator, is effective in treatment of coronary atherosclerotic heart disease with rare side effects in the clinic for long years. Interestingly, studies have shown that TMZ protects against several acute kidney injuries (AKI). However, the effect of TMZ on chronic kidney diseases (CKD) remains unknown. This study aimed to investigate the role of TMZ in diabetic nephropathy (DN) and its potential mechanisms. A rat model of DN was established in male Sprague-Dawley rats by streptozotocin (STZ) intraperitoneal injection. Experimental rats were separated into three groups: control, DN and DN + TMZ treatment. Metabolic parameters, pathological features and renal function markers were evaluated after 20 weeks of diabetes induction. In vitro experiments, the effect of TMZ on high fat and high glucose (HFG) induced or TGFβ1-induced epithelial-to-mesenchymal transition (EMT) was examined in HK-2 cells. Our results showed that TMZ could maintain renal function without affecting hemodynamic and plasma metabolic levels in diabetic rats. The effect was associated with a reversion of pathological progression of DN, especially for tubulointerstitial fibrosis. EMT is an important contributor to renal fibrosis. In this study, we investigated the role of TMZ in the process of EMT in DN. Mechanistically; TMZ attenuated HFG-induced EMT by relieving oxidative stress via deacetylation forkhead box O1 (FoxO1) in a Sirt1-dependent pathway. And it suppressed TGFβ1-induced EMT by deacetylating Smd4 in a Sirt1-dependent manner. Moreover, our study found that TMZ upregulated Sirt1 expression by increasing the expression of nicotinamide phosphoribosyl transferase (Nampt), which is a rate limiting enzyme for nicotinamide adenine dinucleotide (NAD+) generation by salvage pathway. And the increased NAD+ promoted Sirt1 expression. In conclusion, TMZ can prevent renal dysfunction and pathogenesis of tubulointerstitial fibrosis in DN, partly by inhibition of EMT via FoxO1/ROS pathway and TGFβ/Smad pathway in a Nampt/NAD+/Sirt1 dependent manner.

Dataset Information

Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats.

Publications

Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats.

Similar Datasets

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