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MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy

(2017) DIABETOLOGIA. 60(6). p.1114-1125
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Abstract
Renal fibrosis is a common complication of diabetic nephropathy and is a major cause of end-stage renal disease. Despite the suggested link between renal fibrosis and microRNA (miRNA) dysregulation in diabetic nephropathy, the identification of the specific miRNAs involved is still incomplete. The aim of this study was to investigate miRNA profiles in the diabetic kidney and to identify potential downstream targets implicated in renal fibrosis. miRNA expression profiling was investigated in the kidneys of 8-month-old Zucker diabetic fatty (ZDF) rats during overt nephropathy. Localisation of the most upregulated miRNA was established by in situ hybridisation. The candidate miRNA target was identified by in silico analysis and its expression documented in the diabetic kidney associated with fibrotic markers. Cultured tubule cells served to assess which of the profibrogenic stimuli acted as a trigger for the overexpressed miRNA, and to investigate underlying epigenetic mechanisms. In ZDF rats, miR-184 showed the strongest differential upregulation compared with lean rats (18-fold). Tubular localisation of miR-184 was associated with reduced expression of lipid phosphate phosphatase 3 (LPP3) and collagen accumulation. Transfection of NRK-52E cells with miR-184 mimic reduced LPP3, promoting a profibrotic phenotype. Albumin was a major trigger of miR-184 expression. Anti-miR-184 counteracted albumin-induced LPP3 downregulation and overexpression of plasminogen activator inhibitor-1. In ZDF rats, ACE-inhibitor treatment limited albuminuria and reduced miR-184, with tubular LPP3 preservation and tubulointerstitial fibrosis amelioration. Albumin-induced miR-184 expression in tubule cells was epigenetically regulated through DNA demethylation and histone lysine acetylation and was accompanied by binding of NF-kappa B p65 subunit to miR-184 promoter. These results suggest that miR-184 may act as a downstream effector of albuminuria through LPP3 to promote tubulointerstitial fibrosis, and offer the rationale to investigate whether targeting miR-184 in association with albuminuria-lowering drugs may be a new strategy to achieve fully anti-fibrotic effects in diabetic nephropathy.
Keywords
Albuminuria, Diabetic nephropathy, Fibrosis, miR-184, Zucker diabetic fatty rats, CELLS, MECHANISMS, EXPRESSION, MIR-184, GENE, PATHOGENESIS, PROTEIN, ACID, DIFFERENTIATION, DEMETHYLATION

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MLA
Zanchi, Cristina et al. “MicroRNA-184 Is a Downstream Effector of Albuminuria Driving Renal Fibrosis in Rats with Diabetic Nephropathy.” DIABETOLOGIA 60.6 (2017): 1114–1125. Print.
APA
Zanchi, C., Macconi, D., Trionfini, P., Tomasoni, S., Rottoli, D., Locatelli, M., Rudnicki, M., et al. (2017). MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy. DIABETOLOGIA, 60(6), 1114–1125.
Chicago author-date
Zanchi, Cristina, Daniela Macconi, Piera Trionfini, Susanna Tomasoni, Daniela Rottoli, Monica Locatelli, Michael Rudnicki, et al. 2017. “MicroRNA-184 Is a Downstream Effector of Albuminuria Driving Renal Fibrosis in Rats with Diabetic Nephropathy.” Diabetologia 60 (6): 1114–1125.
Chicago author-date (all authors)
Zanchi, Cristina, Daniela Macconi, Piera Trionfini, Susanna Tomasoni, Daniela Rottoli, Monica Locatelli, Michael Rudnicki, Jo Vandesompele, Pieter Mestdagh, Giuseppe Remuzzi, Ariela Benigni, and Carlamaria Zoja. 2017. “MicroRNA-184 Is a Downstream Effector of Albuminuria Driving Renal Fibrosis in Rats with Diabetic Nephropathy.” Diabetologia 60 (6): 1114–1125.
Vancouver
1.
Zanchi C, Macconi D, Trionfini P, Tomasoni S, Rottoli D, Locatelli M, et al. MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy. DIABETOLOGIA. 2017;60(6):1114–25.
IEEE
[1]
C. Zanchi et al., “MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy,” DIABETOLOGIA, vol. 60, no. 6, pp. 1114–1125, 2017.
@article{8524596,
  abstract     = {Renal fibrosis is a common complication of diabetic nephropathy and is a major cause of end-stage renal disease. Despite the suggested link between renal fibrosis and microRNA (miRNA) dysregulation in diabetic nephropathy, the identification of the specific miRNAs involved is still incomplete. The aim of this study was to investigate miRNA profiles in the diabetic kidney and to identify potential downstream targets implicated in renal fibrosis. 
miRNA expression profiling was investigated in the kidneys of 8-month-old Zucker diabetic fatty (ZDF) rats during overt nephropathy. Localisation of the most upregulated miRNA was established by in situ hybridisation. The candidate miRNA target was identified by in silico analysis and its expression documented in the diabetic kidney associated with fibrotic markers. Cultured tubule cells served to assess which of the profibrogenic stimuli acted as a trigger for the overexpressed miRNA, and to investigate underlying epigenetic mechanisms. 
In ZDF rats, miR-184 showed the strongest differential upregulation compared with lean rats (18-fold). Tubular localisation of miR-184 was associated with reduced expression of lipid phosphate phosphatase 3 (LPP3) and collagen accumulation. Transfection of NRK-52E cells with miR-184 mimic reduced LPP3, promoting a profibrotic phenotype. Albumin was a major trigger of miR-184 expression. Anti-miR-184 counteracted albumin-induced LPP3 downregulation and overexpression of plasminogen activator inhibitor-1. In ZDF rats, ACE-inhibitor treatment limited albuminuria and reduced miR-184, with tubular LPP3 preservation and tubulointerstitial fibrosis amelioration. Albumin-induced miR-184 expression in tubule cells was epigenetically regulated through DNA demethylation and histone lysine acetylation and was accompanied by binding of NF-kappa B p65 subunit to miR-184 promoter. 
These results suggest that miR-184 may act as a downstream effector of albuminuria through LPP3 to promote tubulointerstitial fibrosis, and offer the rationale to investigate whether targeting miR-184 in association with albuminuria-lowering drugs may be a new strategy to achieve fully anti-fibrotic effects in diabetic nephropathy.},
  author       = {Zanchi, Cristina and Macconi, Daniela and Trionfini, Piera and Tomasoni, Susanna and Rottoli, Daniela and Locatelli, Monica and Rudnicki, Michael and Vandesompele, Jo and Mestdagh, Pieter and Remuzzi, Giuseppe and Benigni, Ariela and Zoja, Carlamaria},
  issn         = {0012-186X},
  journal      = {DIABETOLOGIA},
  keywords     = {Albuminuria,Diabetic nephropathy,Fibrosis,miR-184,Zucker diabetic fatty rats,CELLS,MECHANISMS,EXPRESSION,MIR-184,GENE,PATHOGENESIS,PROTEIN,ACID,DIFFERENTIATION,DEMETHYLATION},
  language     = {eng},
  number       = {6},
  pages        = {1114--1125},
  title        = {MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy},
  url          = {http://dx.doi.org/10.1007/s00125-017-4248-9},
  volume       = {60},
  year         = {2017},
}

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