MicroRNAs: potential therapeutic targets in diabetic complications of the cardiovascular and renal systems

Figueira, Miriam F.; Monnerat, Gustavo; Medei, Emiliano; Carvalho, Adriana Bastos; Morales, Marcelo M.; Lamas, Marcos; Fonseca, Rodrigo Nunes da; Souza-Menezes, Jackson

doi:10.1111/apha.12316

Cited by 28 publications

(25 citation statements)

References 64 publications

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“…2014; Figueira et al. 2014; Pugliese 2014; Kato and Natarajan 2015). Diabetic kidney pathology, especially the initial phase, is not completely understood and more research in this field is relevant to prevent renal deterioration and to reduce mortality in patients with diabetes.…”

Section: Introductionmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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Diabetic nephropathy (DN) occurs in around 40% of those with diabetes. Proteinuria is the main characteristic of DN and develops as a result of increased permeability of the glomerulus capillary wall and/or decreased proximal tubule endocytosis. The goal of this work was to evaluate renal function and the expression of megalin, cubilin, CFTR (cystic fibrosis transmembrane conductance regulator), and ClC‐5 in the proximal tubule and renal cortex of rats with type 1 diabetes. Male Wistar rats were randomly assigned to control (CTRL) and diabetic (DM) groups for 4 weeks. Renal function was assessed in 24‐h urine sample by calculating clearance and fractional excretion of solutes. The RNA and protein contents of ClC‐5, CFTR, megalin, and cubilin were determined in the renal proximal tubule and cortex using real‐time polymerase chain reaction and western blotting techniques, respectively. The results showed higher creatinine clearance and higher urinary excretion of proteins, albumin, and transferrin in the DM group than in the CTRL group. Furthermore, the renal cortex and proximal tubule of diabetic animals showed downregulation of megalin, cubilin, ClC‐5, and CFTR, critical components of the endocytic apparatus. These data suggest dysfunction in proximal tubule low‐molecular‐weight endocytosis and protein glomerulus filtration in the kidney of diabetic rats.

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Section: Introductionmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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“…Recent studies have demonstrated an association between miRs and DCM (23)(24)(25). The expression level of miR in the hearts of patients with DCM was found to be different when compared with that of healthy individuals (25,26).…”

Section: Introductionmentioning

confidence: 99%

Role of microRNAs in the pathogenesis of diabetic cardiomyopathy

Liu

2017

Biomedical Reports

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Abstract. The morbidity of diabetes mellitus has been increasing annually. As a progressive metabolic disorder, chronic complications occur in the late stage of diabetes. In addition, cardiovascular diseases account for the major cause of morbidity and mortality among the diabetic population worldwide. Diabetic cardiomyopathy (DCM) is a type of diabetic heart disease. Patients with DCM show symptoms and signs of heart failure while no specific cause, such as coronary disease, hypertension, alcohol consumption, or other structural heart diseases has been identified. The pathogenesis of DCM is complex and has not been well understood until recently. MicroRNAs (miRs) belong to a novel family of highly conserved, short, non-coding, single-stranded RNA molecules that regulate transcriptional and post-transcriptional gene expression. Furthermore, recent studies have demonstrated an association between miRs and DCM. In the current review, the role of miRs in the pathogenesis of DCM is summarized. It was concluded that miRs contribute to the regulation of cardiomyocyte hypertrophy, myocardial fibrosis, cardiomyocyte apoptosis, mitochondrial dysfunction, myocardial electrical remodeling, epigenetic modification and various other pathophysiological processes of DCM. These studies may provide novel insights into targets for prevention and treatment of the disease.

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“…In HK-2 cells, miR-29a acts as a repressor to fine-tune collagen expression and that the reduction of miR-29a caused by high glucose may increase the risk of excess collagen deposition [17]. The potential use of differentially expressed miRNAs may be as novel diagnostic biomarkers and therapeutic targets in DKD [18, 19]. However, the role of miRNA in EMT of HK-2 cells in DKD remains unclear.…”

Section: Introductionmentioning

confidence: 99%

miR302a-3p May Modulate Renal Epithelial-Mesenchymal Transition in Diabetic Kidney Disease by Targeting ZEB1

Tang

Zheng

Yan

et al. 2017

Nephron

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Background: Recent study found that microRNA (miRNA) are involved in diabetic kidney disease (DKD). The objective of this study is to determine the role of miR302a-3p in the process of renal epithelial-mesenchymal transition (EMT) in DKD. Methods: The miRNA expression profiling of the cell line stimulated by high glucose was performed by a microarray analysis. Then real-time polymerase chain reaction (PCR) were used to determine the expression of one of the miRNAs significantly upregulated in cell line stimulated by high glucose, miR302a-3p. miR302a-3p mimics and inhibitor were transfected to HK-2 cells following exposure to high glucose and normal glucose, respectively. The expressions of E-cadherin, vimentin, and Zinc finger E-box-binding protein 1 (ZEB-1) were determined by real-time PCR and Western blot. Finally, the levels of miR302a-3p in the plasma of DKD patients were detected by real-time PCR, and then the relationship of miR302a-3p and urinary albumin excretion (UAE) or estimated glomerular filtration rate (eGFR) was analyzed. Results: The expression of miR-302a-3p, 513a-5p, 1291 and the other 17 miRNA were increased significantly in HK-2 cell line after high glucose stimulation; on the other hand, miRNA490–3p, 638, 3203 and the other 19 miRNA were decreased significantly. In vitro, miR-302a-3p expression in HG group increased at 6 h and ascended to the highest level at 12 and 24 h and then gradually decreased from 48 to 72 h. More interesting, ZEB1 protein expression had an opposite change, which gradually decreased from 6 to 24 h and then gradually increased from 48 to 72 h. Moreover, overexpression of miR-302a-3p suppressed expression of ZEB1 in the post-transcriptional level and reversed high glucose-mediated downregulation of E-cadherin and upregulation of vimentin. Meanwhile, loss of miR-302a-3p expression can lead to EMT of HK-2 cells just as high glucose stimulation. Further study demonstrated that the expression of circulating miR-302a-3p was significantly increased in the diabetes mellitus (DM) with normoalbuminuria (DM group, n = 22) compared with control (healthy persons, n = 30) and then decreased in DM with microalbuminuria (DNE group, n = 20). Furthermore, its expression in DM with macroalbuminuria (DNC group, n = 18) was decreased significantly compared with DM group. Circulating miR-302a-3p had negative relevance with UAE in DNE group (r = –0.649, p = 0.002) and DNC group (r = –0.681, p = 0.006). Circulating miR-302a-3p had positive relevance with eGFR in DNC group (r = 0.486, p = 0.041). Conclusions: These findings suggest that miR-302a-3p may play a protective role by targeting ZEB1 in renal EMT in DKD. In view of these findings, it is conceivable that miR-302a-3p may serve as a potential novel target in pre-EMT states for the amelioration renal fibrosis seen in DKD.

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MicroRNAs: potential therapeutic targets in diabetic complications of the cardiovascular and renal systems

Cited by 28 publications

References 64 publications

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

Role of microRNAs in the pathogenesis of diabetic cardiomyopathy

miR302a-3p May Modulate Renal Epithelial-Mesenchymal Transition in Diabetic Kidney Disease by Targeting ZEB1

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