Abstract
Aims/hypothesisRenal 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.MethodsmiRNA 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.ResultsIn 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-κB p65 subunit to miR-184 promoter.Conclusions/interpretationThese 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.
Highlights
Diabetic nephropathy is one of the major microvascular complications of diabetes and the leading cause of chronic kidney disease and end-stage renal disease (ESRD) throughout the world [1, 2]
Conclusions/interpretation These results suggest that miR-184 may act as a downstream effector of albuminuria through lipid phosphate phosphatase 3 (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
Studies in animal models of diabetes have contributed to defining intracellular and molecular pathways driving renal fibrosis, which include the activation of the renin–angiotensin system, protein kinase C, TGF-β1 and monocyte chemoattractant protein-1 (MCP-1) and the upregulation of plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF)/CCN2, collagen and cytokines [8,9,10,11]
Summary
Diabetic nephropathy is one of the major microvascular complications of diabetes and the leading cause of chronic kidney disease and end-stage renal disease (ESRD) throughout the world [1, 2]. A number of miRNAs have been shown to be relevant to fibrotic processes in diabetic nephropathy, including miR-29 and miR-200 families, miR192 and miR-21 [14,15,16,17]. These miRNAs are regulated by TGF-β in renal cells, and normalisation of their expression ameliorated fibrosis in in vitro and in vivo models of diabetes, suggesting that targeting these miRNAs could be a way to improve diabetic nephropathy downstream of TGF-β [16]. The in vivo findings were mainly obtained in early stages of type 1 and type 2 diabetic nephropathy [14, 16]
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